α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors

ABSTRACT

α- and β-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.

RELATED APPLICATION

This application is a continuation of Ser. No. 09/798,255 filed Mar. 5,2001, now U.S. Pat. No. 6,417,387 which is a continuation of Ser. No.09/288,080 filed Apr. 8, 1999, now U.S. Pat. No. 6,248,775 which is acontinuation of Ser. No. 08/294,468 filed Aug. 23, 1994 now U.S. Pat.No. 5,968,942 which is a continuation-in-part of Ser. No. 08/204,827filed Mar. 2, 1994, now U.S. Pat. No. 6,060,476 which is acontinuation-in-part of International Application PCT/US93/07814 filedAug. 24, 1993 and Ser. No. 08/110,911, now U.S. Pat. No. 5,843,946 filedAug. 24, 1993, which is a continuation-in-part of Ser. No. 07/934,984filed Aug. 25, 1992, now abandoned, each of which is incorporated hereinby reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to retroviral protease inhibitors and,more particularly, relates to novel compounds and a composition andmethod for inhibiting retroviral proteases. This invention, inparticular, relates to sulfonamide-containing hydroxyethylamine proteaseinhibitor compounds, a composition and method for inhibiting retroviralproteases such as human immunodeficiency virus (HIV) protease and fortreating a retroviral infection, e.g., an HIV infection. The subjectinvention also relates to processes for making such compounds as well asto intermediates useful in such processes.

2. Related Art

During the replication cycle of retroviruses, gag and gag-pol genetranscription products are translated as proteins. These proteins aresubsequently processed by a virally encoded protease (or proteinase) toyield viral enzymes and structural proteins of the virus core. Mostcommonly, the gag precursor proteins are processed into the coreproteins and the pol precursor proteins are processed into the viralenzymes, e.g., reverse transcriptase and retroviral protease. It hasbeen shown that correct processing of the precursor proteins by theretroviral protease is necessary for assembly of infectious virons. Forexample, it has been shown that frameshift mutations in the proteaseregion of the pol gene of HIV prevents processing of the gag precursorprotein. It has also been shown through site-directed mutagenesis of anaspartic acid residue in the HIV protease active site that processing ofthe gag precursor protein is prevented. Thus, attempts have been made toinhibit viral replication by inhibiting the action of retroviralproteases.

Retroviral protease inhibition typically involves a transition-statemimetic whereby the retroviral protease is exposed to a mimetic compoundwhich binds (typically in a reversible manner) to the enzyme incompetition with the gag and gag-pol proteins to thereby inhibitspecific processing of structural proteins and the release of retroviralprotease itself. In this manner, retroviral replication proteases can beeffectively inhibited.

Several classes of compounds have been proposed, particularly forinhibition of proteases, such as for inhibition of HIV protease. Suchcompounds include hydroxyethylamine isosteres and reduced amideisosteres. See, for example, EP O 346 847; EP O 342,541; Roberts et al,“Rational Design of Peptide-Based Proteinase Inhibitors, “Science, 248,358 (1990); and Erickson et al, “Design Activity, and 2.8 Å CrystalStructure of a C₂ Symmetric Inhibitor Complexed to HIV-1 Protease,”Science, 249, 527 (1990).

Several classes of compounds are known to be useful as inhibitors of theproteolytic enzyme renin. See, for example, U.S. Pat. No. 4,599,198;U.K. 2,184,730; G.B. 2,209,752; EP O 264 795; G.B. 2,200,115 and U.S.SIR H725. Of these, G.B. 2,200,115, GB 2,209,752, EP O 264,795, U.S. SIRH725 and U.S. Pat. No. 4,599,198 disclose urea-containinghydroxyethylamine renin inhibitors. EP 468 641 discloses renininhibitors and intermediates for the preparation of the inhibitors,which include sulfonamide-containing hydroxyethylamine compounds, suchas3-(t-butoxycarbonyl)amino-cyclohexyl-1-(phenylsulfonyl)amino-2(5)-butanol.G.B. 2,200,115 also discloses sulfamoyl-containing hydroxyethylaminerenin inhibitors, and EP 0264 795 discloses certainsulfonamide-containing hydroxyethylamine renin inhibitors. However, itis known that, although renin and HIV proteases are both classified asaspartyl proteases, compounds which are effective renin inhibitorsgenerally cannot be predicted to be effective HIV protease inhibitors.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is directed to virus inhibiting compounds andcompositions. More particularly, the present invention is directed toretroviral protease inhibiting compounds and compositions, to a methodof inhibiting retroviral proteases, to processes for preparing thecompounds and to intermediates useful in such processes. The subjectcompounds are characterized as sulfonamide-containing hydroxyethylamineinhibitor compounds.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a retroviralprotease inhibiting compound of the formula:

or a pharmaceutically acceptable salt, prodrug or ester thereof,wherein:

R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxycarbonyl, heteroaroyl, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl,heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoalkanoyl, andmono- and disubstituted aminocarbonyl and mono- and disubstitutedaminoalkanoyl radicals wherein the substituents are selected from alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, heterocycloalkyalkyl radicals, or where saidaminocarbonyl and aminoalkanoyl radicals are disubstituted, saidsubstituents along with the nitrogen atom to which they are attachedform a heterocycloalkyl or heteroaryl radical;

R′ represents hydrogen, radicals as defined for R³ or R″SO₂— wherein R″represents radicals as defined for R³; or R and R′ together with thenitrogen to which they are attached represent heterocycloalkyl andheteroaryl radicals;

R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,—CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),—C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkylradicals, and amino acid side chains selected from asparagine, S-methylcysteine and the sulfoxide (SO) and sulfone (SO₂) derivatives thereof,isoleucine, allo-isoleucine, alanine, leucine, tert-leucine,phenylalanine, ornithine, histidine, norleucine, glutamine, threonine,allo-threonine, serine, O-alkyl serine, aspartic acid, beta-cyanoalanine and valine side chains;

R^(1′) and R^(1″) independently represent hydrogen and radicals asdefined for R¹, or one of R^(1′) and R^(1″), together with R¹ and thecarbon atoms to which R¹, R^(1′) and R^(1″) are attached, represent acycloalkyl radical;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, —NO₂, —CN, —CF₃, —OR⁹ and —SR⁹,wherein R⁹ represents hydrogen and alkyl radicals, and halogen radicals;

R³ represents hydrogen, alkyl, haloalkyl, alkenyl, alkynyl,hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl,heteroaralkyl, aminoalkyl and mono- and disubstituted aminoalkylradicals, wherein said substituents are selected from alkyl, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case ofa disubstituted aminoalkyl radical, said substituents along with thenitrogen atom to which they are attached, form a heterocycloalkyl or aheteroaryl radical;

R⁴ represents radicals as defined by R³ except for hydrogen;

R⁶ represents hydrogen and alkyl radicals;

x represents 0, 1 or 2;

t represents either 0 or 1; and

Y represents O, S and NR¹⁵ wherein R¹⁵ represents hydrogen and radicalsas defined for R³.

A family of compounds of particular interest within Formula I arecompounds embraced by Formula II:

wherein:

R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, alkyl,alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstitutedaminocarbonyl and mono- and disubstituted aminoalkanoyl radicals whereinthe substituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,—CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),—C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkylradicals, and amino acid side chains selected from asparagine, S-methylcysteine and the sulfoxide (SO) and sulfone (SO₂) derivatives thereof,isoleucine, allo-isoleucine, alanine, leucine, tert-leucine,phenylalanine, ornithine, histidine, norleucine, glutamine, threonine,allo-threonine, serine, O-methyl serine, aspartic acid, beta-cyanoalanine and valine side chains;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, —NO₂, —C≡N, CF₃, —OR⁹, —SR⁹,wherein R⁹ represents hydrogen and alkyl radicals;

R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical; and

R⁴ represents radicals as defined by R³.

A more preferred family of compounds within Formula II consists ofcompounds wherein:

R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, alkyl,alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstitutedaminocarbonyl and mono- and disubstituted aminoalkanoyl radicals whereinthe substituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents CH₂C(O)NHCH₃, C(CH₃)₂(SCH₃), C(CH₃)₂(S[O]CH₃),C(CH₃)₂(S[O]₂CH₃), alkyl, alkenyl and alkynyl radicals, and amino acidside chains selected from the group consisting of asparagine, valine,threonine, allo-threonine, isoleucine, tert-leucine, S-methyl cysteineand the sulfone and sulfoxide derivatives thereof, alanine, andallo-isoleucine;

R² represents alkyl, cycloalkylalkyl and aralkyl radicals, whichradicals are optionally substituted with halogen radicals and radicalsrepresented by the formula —OR⁹ and —SR⁹ wherein R⁹ represents alkylradicals; and

R³ and R⁴ independently represent alkyl, alkenyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, aralkyl and heteroaralkyl radicals.

Of highest interest are compounds within Formula II wherein

R represents alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cyclolkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl,aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyland mono- and disubstituted aminoalkanoyl radicals wherein thesubstituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents CH₂C(O)NHCH₃, C(CH₃)₂(SCH₃), C(CH₃)₂(S[O]CH₃),C(CH₃)₂(S[O]₂CH₃), methyl, propargyl, t-butyl, isopropyl and sec-butylradicals, and amino acid side chains selected from the group consistingof asparagine, valine, S-methyl cysteine, allo-iso-leucine, iso-leucine,and beta-cyano alanine side chains;

R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl, benzyl, 4-fluorobenzyl,2-naphthylmethyl and cyclohexylmethyl radicals;

R³ represents isoamyl, n-butyl, isobutyl and cyclohexyl radicals; and

R⁴ represents phenyl, -substituted phenyl and methyl radicals.

Another family of compounds of particular interest within Formula I arecompounds embraced by Formula III:

wherein:

R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, alkyl,alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstitutedaminocarbonyl and mono- and disubstituted aminoalkanoyl radicals whereinthe substituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,—CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),—C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkylradicals, and amino acid side chains selected from asparagine, S-methylcysteine and the sulfoxide (SO) and sulfone (SO₂) derivatives thereof,isoleucine, allo-isoleucine, alanine, leucine, tert-leucine,phenylalanine, ornithine, histidine, norleucine, glutamine, threonine,allo-threonine, serine, aspartic acid, beta-cyano alanine and valineside chains;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radicals, —NO₂, —C≡N, CF_(3,) —OR⁹,—SR⁹, wherein R⁹ represents hydrogen and alkyl;

R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical; and

R⁴ represents radicals as defined by R³.

A more preferred family of compounds within Formula III consists ofcompounds wherein

R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, alkyl,alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstitutedaminocarbonyl and mono- and disubstituted aminoalkanoyl radicals whereinthe substituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents hydrogen, alkyl and alkenyl radicals, and amino acid sidechains selected from the group consisting of asparagine, valine,threonine, allo-threonine, isoleucine, tert-leucine, S-methyl cysteineand the sulfone and sulfoxide derivatives thereof, alanine, andallo-isoleucine;

R² represents alkyl, cycloalkylalkyl and aralkyl radicals, whichradicals are optionally substituted with halogen radicals and radicalsrepresented by the formula —OR⁹ and —SR⁹ wherein R⁹ represents hydrogenand alkyl and halogen radicals; and

R³ and R⁴ independently represent alkyl, alkenyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, aralkyl, heteroaryl and heteroaralkyl radicals.

Of highest interest are compounds within Formula III wherein

R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl,aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyland mono- and disubstituted aminoalkanoyl radicals wherein thesubstituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents hydrogen, methyl, propargyl, t-butyl, isopropyl andsec-butyl radicals, and amino acid side chains selected from the groupconsisting of asparagine, valine, S-methyl cysteine, allo-iso-leucine,iso-leucine, threonine, serine, aspartic acid, beta-cyano alanine, andallo-threonine side chains;

R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl, benzyl, 4-fluorobenzyl,2-naphthylmethyl and cyclohexylmethyl radicals; and

R³ represents alkyl, cyclohexyl, isobutyl, isoamyl, and n-butylradicals; and

R⁴ represents methyl, phenyl and substituted phenyl radicals wherein thesubstituents are selected from halo, alkoxy, hydroxy, nitro and aminosubstituents.

Another family of compounds of particular interest within Formula I arecompounds embraced by Formula IV:

wherein:

R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, alkyl,alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstitutedaminocarbonyl and mono- and disubstituted aminoalkanoyl radicals whereinthe substituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,—CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S[O]CH₃),—C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl, alkynyl and cycloalkylradicals, and amino acid side chains selected from asparagine, S-methylcysteine and the sulfoxide (SO) and sulfone (SO₂) derivatives thereof,isoleucine, allo-isoleucine, alanine, leucine, tert-leucine,phenylalanine, ornithine, histidine, norleucine, glutamine, threonine,allo-threonine, serine, aspartic acid, beta-cyano alanine and valineside chains;

R^(1′) and R^(1″) independently represent hydrogen and radicals asdefined for R¹, or one of R^(1′) and R^(1″), together with R¹ and thecarbon atoms to which R¹, R^(1′) and R^(1″) are attached, represent acycloalkyl radical;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, —NO₂, —C≡N, CF₃, —OR⁹ and —SR⁹,wherein R⁹ represents hydrogen and alkyl radicals;

R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical; and

R⁴ represents radicals as defined by R³.

A more preferred family of compounds within Formula IV consists ofcompounds wherein

R represents an arylalkanoyl, heteroaroyl, aryloxyalkanoyl,aryloxycarbonyl, alkanoyl, aminocarbonyl, mono-substitutedaminoalkanoyl, or disubstituted aminoalkanoyl, or mono- ordialkylaminocarbonyl radical;

R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached represent aheterocycloalkyl or heteroaryl radical;

R¹, R^(1′) and R^(1″) independently represent hydrogen and alkylradicals having from 1 to about 4 carbon atoms, alkenyl, alkynyl,aralkyl radicals, and radicals represented by the formula —CH₂C(O)R″ or—C(O)R″ wherein R″ represents R³⁸, —NR³⁸R³⁹ and OR³⁸ wherein R³⁸ and R³⁹independently represent hydrogen and alkyl radicals having from 1 toabout 4 carbon atoms;

R² represents alkyl, cycloalkylalkyl and aralkyl radicals, whichradicals are optionally substituted with halogen radicals and radicalsrepresented by the formula —OR⁹ and —SR⁹ wherein R⁹ represents hydrogenand alkyl radicals; and

R³ and R⁴ independently represent alkyl, alkenyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, aralkyl, heteroaryl and heteroaralkyl radicals.

Of highest interest are compounds of Formula IV wherein:

R represents an arylalkanoyl, aryloxycarbonyl, aryloxyalkanoyl,alkanoyl, aminocarbonyl, mono-substituted aminoalkanoyl, ordisubstituted aminoalkanoyl, or mono- or dialkylaminocarbonyl radical;

R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached represent aheterocycloalkyl or heteroaryl radical;

R¹, R^(1′) and R^(1″) independently represent hydrogen, methyl, ethyl,benzyl, phenylpropyl and propargyl radicals;

R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl, benzyl, 4-fluorobenzyl,2-naphthylmethyl and cyclohexylmethyl radicals;

R³ represents alkyl, cyclohexyl, isobutyl, isoamyl and n-butyl radicals;and

R⁴ represents methyl, phenyl and substituted phenyl radicals wherein thesubstituents are selected from halo, alkoxy, amino and nitrosubstituents.

As utilized herein, the term “alkyl”, alone or in combination, means astraight-chain or branched-chain alkyl radical containing from 1 toabout 10 carbon atoms, preferably from 1 to about 8 carbon atoms, morepreferably 1-5 carbon atoms. Examples of such radicals include methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,pentyl, iso-amyl, hexyl, octyl and the like. The term “alkenyl”, aloneor in combination, means a straight-chain or branched-chain hydrocarbonradial having one or more double bonds and containing from 2 to about 18carbon atoms, preferably from 2 to about 8 carbon atoms, more preferablyfrom 2 to about 5 carbon atoms. Examples of suitable alkenyl radicalsinclude ethenyl, propenyl, alkyl, 1,4-butadienyl and the like. The term“alkynyl”, alone or in combination, means a straight-chain or branchedchain hydrocarbon radical having one or more triple bonds and containingfrom 2 to about 10 carbon atoms, more preferably from 2 to about 5carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl,(propargyl), butynyl and the like. The term “alkoxy”, alone or incombination, means an alkyl ether radical wherein the term alkyl is asdefined above. Examples of suitable alkyl ether radicals includemethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy and the like. The term “cycloalkyl”, alone or incombination, means a saturated or partially saturated monocyclic,bicyclic or tricyclic alkyl radical wherein each cyclic moiety containsfrom about 3 to about 8 carbon atoms, more preferably from about 3 toabout 6 carbon atoms. Examples of such cycloalkyl radicals includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term“cycloalkylalkyl” means an alkyl radical as defined above which issubstituted by a cycloalkyl radical as defined above. Examples of suchcycloalkylalkyl radicals include cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl,1-cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl,cyclobutylpropyl, cyclopentylpropyl, cyclohexylbutyl and the like. Theterm “aryl”, alone or in combination, means a phenyl or naphthyl radicalwhich optionally carries one or more substituents selected from alkyl,alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl, carboxy,alkoxycarbonyl, cycloalkyl, heterocycloalkyl, amido, mono and dialkylsubstituted amino, mono and dialkyl substituted amido and the like, suchas phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl,3-methyl-4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 3-nitrophenyl,3-aminophenyl, 3-acetamidophenyl, 4-acetamidophenyl,2-methyl-3-acetamidophenyl, 2-methyl-3-aminophenyl,3-methyl-4-aminophenyl, 2-amino-3-methylphenyl,2,4-dimethyl-3-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl,1-naphthyl, 2-naphthyl, 3-amino-1-naphthyl, 2-methyl-3-amino-1-naphthyl,6-amino-2-naphthyl, 4,6-dimethoxy-2-naphthyl and the like. The terms“aralkyl” and “aralkoxy”, alone or in combination, means an alkyl oralkoxy radical as defined above in which at least one hydrogen atom isreplaced by an aryl radical as defined above, such as benzyl, benzyloxy,2-phenylethyl, dibenzylmethyl, hydroxyphenylmethyl, methylphenylmethyl,and the like. The term “aralkoxycarbonyl”, alone or in combination,means a radical of the formula aralkyl-O—C(O)— in which the term“aralkyl” has the significance given above. Examples of anaralkoxycarbonyl radical are benzyloxycarbonyl and4-methoxyphenylmethoxycarbonyl. The term “aryloxy” means a radical ofthe formula aryl-O— in which the term aryl has the significance givenabove. The term “alkanoyl”, alone or in combination, means an acylradical derived from an alkanecarboxylic acid, examples of which includeacetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, and the like. Theterm “cycloalkylcarbonyl” means an acyl group derived from a monocyclicor bridged cycloalkanecarboxylic acid such as cyclopropylcarbonyl,cyclohexylcarbonyl, adamantylcarbonyl, and the like, or from abenz-fused monocyclic cycloalkanecarboxylic acid which is optionallysubstituted by one or more substituents selected from alkyl, alkoxy,halogen, hydroxy, amino, nitro, cyano, haloalkyl, carboxy,alkoxycarbonyl, cycloalkyl, heterocycloalkyl, alkanoylamino, amido, monoand dialkyl substituted amino, mono and dialkyl substituted amido andthe like, such as 1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. The term “aralkanoyl” meansan acyl radical derived from an aryl-substituted alkanecarboxylic acidsuch as phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl),4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl,4-aminohydrocinnamoyl,4-methoxyhydrocinnamoyl, and the like. The term“aroyl” means an acyl radical derived from an arylcarboxylic acid, arylhaving the meaning given above. Examples of such arylcarboxylic acidradicals include substituted and unsubstituted benzoic or naphthoic acidsuch as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.The terms “heterocyclyl” and “heterocycloalkyl,” alone or incombination, mean a saturated or partially unsaturated monocyclic,bicyclic or tricyclic heterocycle having preferably 3 to 12 ringmembers, more preferably 5 to 10 ring members and most preferably 5 to 6ring members, which contains one or more heteroatom ring membersselected from nitrogen, oxygen and sulphur, and which is optionallysubstituted on one or more carbon atoms by halogen, alkyl, alkoxy,hydroxy, oxo, aryl, aralkyl and the like, and/or on a secondary nitrogenatom (i.e., —NH—) by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, phenylor phenylalkyl and/or on a tertiary nitrogen atom (i.e., ═N—) by oxido.Heterocycloalkyl and heterocyclyl also includes benz-fused monocycliccycloalkyl groups having at least one such heteroatom. Heterocycloalkyland heterocyclyl in addition to sulfur and nitrogen also includessulfones, sulfoxides and N-oxides of tertiary nitrogen containingheterocycloalkyl groups. The term “heteroaryl”, alone or in combination,means an aromatic monocyclic, bicyclic, or tricyclic heterocyclyl(heterocycloalkyl) radical as defined above and is optionallysubstituted as defined above with respect to the definitions of aryl andheterocyclyl (heterocycloalkyl). Examples of such heterocyclyl(heterocycloalkyl) and heteroaryl groups are pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyl (e.g.,imidazol 4-yl, 1-benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl,pyridyl, (e.g., 2-(1-piperidinyl)pyridyl and 2-(4-benzylpiperazin-1-yl-1-pyridinyl), pyrazinyl, pyrimidinyl, furyl,tetrahydrofuryl, thienyl, triazolyl, oxazolyl, thiazolyl, indolyl (e.g.,2-indolyl, etc.), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl,1-oxido-2-quinolinyl, etc.), isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, etc.), tetrahydroquinolinyl (e.g.,1,2,3,4-tetrahydro-2-quinolyl, etc.), 1,2,3,4-tetrahydroisoquinolinyl(e.g., 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, etc.), quinoxalinyl,β-carbolinyl, 2-benzofurancarbonyl, 1-, 2-,4- or 5-benzimidazolyl, andthe like. The term “cycloalkylalkoxycarbonyl” means an acyl groupderived from a cycloalkylalkoxycarboxylic acid of the formulacycloalkylalkyl-O—COOH wherein cycloalkylalkyl has the meaning givenabove. The term “aryloxyalkanoyl” means an acyl radical of the formulaaryl-O-alkanoyl wherein aryl and alkanoyl have the meaning given above.The term “heterocycloalkoxycarbonyl” means an acyl group derived fromheterocyclyl-O—COOH wherein heterocyclyl is as defined above. The term“heterocycloalkylalkanoyl” is an acyl radical derived from aheterocycloalkyl-substituted alkylcarboxylic acid whereinheterocycloalkyl has the meaning given above. The term“heterocycloalkylalkoxycarbonyl” means an acyl radical derived from aheterocycloalkyl-substituted alkyl-O—COOH wherein heterocycloalkyl hasthe meaning given above. The term “heteroaryloxycarbonyl” means an acylradical derived from a carboxylic acid represented by heteroaryl-O—COOHwherein heteroaryl has the meaning given above. The term “aminocarbonyl”alone or in combination, means an amino-substituted carbonyl (carbamoyl)group wherein the amino group can be a primary, secondary or tertiaryamino group containing substituents selected from alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl radicals and the like. The term“aminoalkanoyl” means an acyl group derived from an amino-substitutedalkylcarboxylic acid wherein the amino group can be a primary, secondaryor tertiary amino group containing substituents selected from alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like. Theterm “halogen” means fluorine, chlorine, bromine or iodine. The term“haloalkyl” means an alkyl radical having the meaning as defined abovewherein one or more hydrogens are replaced with a halogen. Examples ofsuch haloalkyl radicals include chloromethyl, 1-bromoethyl,fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl andthe like. The term “leaving group” generally refers to groups readilydisplaceable by a nucleophile, such as an amine, a thiol or an alcoholnucleophile. Such leaving groups are well known in the art. Examples ofsuch leaving groups include, but are not limited to,N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates,tosylates and the like. Preferred leaving groups are indicated hereinwhere appropriate. The term “amino acid side chain” means the side chaingroup, including the stereochemistry of the carbon to which it isattached, attached to the naturally occurring amino acid whichdistinguishes the amino acid from glycine. For example, the amino acidside chain of alanine is methyl, of histidine is imidazolylmethyl andphenylalanine is benzyl, and the attachment of such side chains to thecompound of this invention retain the naturally occurringstereochemistry of the carbon to which it is attached. The followingexample illustrates the definition:

Procedures for preparing the compounds of Formula I are set forth below.It should be noted that the general procedure is shown as it relates topreparation of compounds having the specified stereochemistry, forexample, wherein the absolute stereochemistry about the hydroxyl groupis designated as (R). However, such procedures are generally applicableto those compounds of opposite configuration, e.g., where thestereochemistry about the hydroxyl group is (S). In addition, thecompounds having the (R) stereochemistry can be utilized to producethose having the (S) stereochemistry. For example, a compound having the(R) stereochemistry can be inverted to the (S) stereochemistry usingwell-known methods.

Preparation of Compounds of Formula I

The compounds of the present invention represented by Formula I abovecan be prepared utilizing the following general procedure. Thisprocedure is schematically shown in the following Schemes I and II:

a) amine b) sulfonyl chloride R⁴SO₂Cl (or anhydride)+acid scavenger c)deprotection d) coupling e) coupling.

a) amine b) sulfonyl chloride R⁴SO₂Cl (or anhydride)+acid scavenger c)deprotection d) coupling e) coupling.

An N-protected chloroketone derivative of an amino acid having theformula:

wherein P represents an amino protecting group, and R² is as definedabove, is reduced to the corresponding alcohol utilizing an appropriatereducing agent. Suitable amino protecting groups are well known in theart and include carbobenzoxy, t-butoxycarbonyl, and the like. Apreferred amino protecting group is carbobenzoxy. A preferredN-protected chloroketone is N-benzyloxycarbonyl-L-phenylalaninechloromethyl ketone. A preferred reducing agent is sodium borohydride.The reduction reaction is conducted at a temperature of from −10° C. toabout 25° C., preferably at about 0° C., in a suitable solvent systemsuch as, for example, tetrahydrofuran, and the like. The N-protectedchloroketones are commercially available, e.g., such as from Bachem,Inc., Torrance, Calif. Alternatively, the chloroketones can be preparedby the procedure set forth in S. J. Fittkau, J. Prakt. Chem., 315, 1037(1973), and subsequently N-protected utilizing procedures which are wellknown in the art.

The halo alcohol can be utilized directly, as described below, or,preferably, is then reacted, preferably at room temperature, with asuitable base in a suitable solvent system to produce an N-protectedamino epoxide of the formula:

wherein P and R² are as defined above. Suitable solvent systems forpreparing the amino epoxide include ethanol, methanol, isopropanol,tetrahydrofuran, dioxane, and the like including mixtures thereof.Suitable bases for producing the epoxide from the reduced chloroketoneinclude potassium hydroxide, sodium hydroxide, potassium t-butoxide, DBUand the like. A preferred base is potassium hydroxide.

Alternatively, a protected amino epoxide can be prepared, such as inco-owned and co-pending PCT Patent Application Serial No. PCT/US93/04804which is incorporated herein by reference, starting with an L-amino acidwhich is reacted with a suitable amino-protecting group in a suitablesolvent to produce an amino-protected L-amino acid ester of the formula:

wherein P³ represents carboxyl-protecting group, e.g., methyl, ethyl,benzyl, tertiary-butyl and the like; R² is as defined above; and P¹ andP² independently are selected from amine protecting groups, includingbut not limited to, arylalkyl, substituted arylalkyl, cycloalkenylalkyland substituted cycloalkenylalkyl, allyl, substituted allyl, acyl,alkoxycarbonyl, aralkoxycarbonyl and silyl. Examples of arylalkylinclude, but are not limited to benzyl, ortho-methylbenzyl, trityl andbenzhydryl, which can be optionally substituted with halogen, alkyl ofC₁-C₈, alkoxy, hydroxy, nitro, alkylene, amino, alkylamino, acylaminoand acyl, or their salts, such as phosphonium and ammonium salts.Examples of aryl groups include phenyl, naphthalenyl, indanyl,anthracenyl, durenyl, 9-(9-phenylfluorenyl) and phenanthrenyl,cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals containingcycloalkyls of C₆-C₁₀. Suitable acyl groups include carbobenzoxy,t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl,butyryl, acetyl, tri-fluoroacetyl, tri-chloroacetyl, phthaloyl and thelike.

Additionally, the P¹ and/or P² protecting groups can form a heterocyclicring with the nitrogen to which they are attached, for example,1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl andthe like and where these heterocyclic groups can further includeadjoining aryl and cycloalkyl rings. In addition, the heterocyclicgroups can be mono-, di- or tri-substituted, e.g., nitrophthalimidyl.The term silyl refers to a silicon atom optionally substituted by one ormore alkyl, aryl and aralkyl groups.

Suitable silyl protecting groups include, but are not limited to,trimethylsilyl, triethylsilyl, tri-isopropylsilyl,tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of the amine functions to provide mono-or bis-disilylamine can provide derivatives of the aminoalcohol, aminoacid, amino acid esters and amino acid amide. In the case of aminoacids, amino acid esters and amino acid amides, reduction of thecarbonyl function provides the required mono- or bis-silyl aminoalcohol.Silylation of the aminoalcohol can lead to the N,N,O-tri-silylderivative. Removal of the silyl function from the silyl ether functionis readily accomplished by treatment with, for example, a metalhydroxide or ammonium flouride reagent, either as a discrete reactionstep or in situ during the preparation of the amino aldehyde reagent.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-buty-dimethylsilyl chloride, phenyldimethylsilyl chlorie,diphenylmethylsilyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Preferably P¹ and P² are independently selected from aralkyl andsubstituted aralkyl. More preferably, each of P¹ and P² is benzyl. Asillustrated in the Examples below, P, P¹ and P² may serve as a nitrogenprotecting group which is later removed in the preparation of compoundsof this invention or may form a part of the final inhibitor structure.For example, benzoyl, benzyloxycarbonyl, t-butoxycarbonyl,pyridylmethoxycarbonyl, tetrahydrofuryloxycarbonyl, pyridylcarbonyl andthe like can used to both protect a nitrogen from undergoing anundesired reaction and also be part of the structure of an active enzymeinhibitor.

The amino-protected L-amino acid ester is then reduced, to thecorresponding alcohol. For example, the amino-protected L-amino acidester can be reduced with diisobutylaluminum hydride at −78° C. in asuitable solvent such as toluene. Preferred reducing agents includelithium aluminium hydride, lithium borohydride, sodium borohydride,borane, lithium tri-ter-butoxyaluminum hydride, borane/THF complex. Mostpreferably, the reducing agent is diisobutylaluminum hydride (DiBAL-H)in toluene. The resulting alcohol is then converted, for example, by wayof a Swern oxidation, to the corresponding aldehyde of the formula:

herein P¹, P² and R² are as defined above. Thus, a dichloromethanesolution of the alcohol is added to a cooled (−75 to −68° C.) solutionof oxalyl chloride in dichloromethane and DMSO in dichloromethane andstirred for 35 minutes.

Acceptable oxidizing reagents include, for example, sulfurtrioxide-pyridine complex and DMSO, oxalyl chloride and DMSO, acetylchloride or anhydride and DMSO, trifluoroacetyl chloride or anhydrideand DMSO, methanesulfonyl chloride and DMSO or tetrahydrothiaphene-S-oxide, toluenesulfonyl bromide and DMSO,trifluoromethanesulfonyl anhydride (triflic anhydride) and DMSO,phosphorus pentachloride and DMSO, dimethylphosphoryl chloride and DMSOand isobutyl chloroformate and DMSO. The axidation conditions reportedby Reetz et al [Angew Chem., 99, p. 1186, (1987)], Angew Chem. Int. Ed.Engl., 26, p. 1141, 1987) employed oxalyl chloride and DMSO at −78° C.

The preferred oxidation method described in this invention is sulfurtrioxide pyridine complex, triethylamine and DMSO at room temperature.This system provides excellent yields of the desired chiral protectedamino aldehyde usable without the need for purification i.e., the needto purify kilograms of intermediates by chromatography is eliminated andlarge scale operations are made less hazardous. Reaction at roomtemperature also eliminated the need for the use of low temperaturereactor which makes the process more suitable for commercial production.

The reaction may be carried out under and inert atmosphere such asnitrogen or argon, or normal or dry air, under atmospheric pressure orin a sealed reaction vessel under positive pressure. Preferred is anitrogen atmosphere. Alternative amine bases include, for example,tri-butyl amine, tri-isopropyl amine, N-methylpiperidine, N-methylmorpholine, azabicyclononane, diisopropylethylamine,2,2,6,6-tetramethylpiperidine, N,N-dimethylaminopyridine, or mixtures ofthese bases. Triethylamine is a preferred base. Alternatives to pureDMSO as solvent include mixtures of DMSO with non-protic or halogenatedsolvents such as tetrahydrofuran, ethyl acetate, toluene, xylene,dichloromethane, ethylene dichloride and the like. Dipolar aproticco-solvents include acetonitrile, dimethylformamide, dimethylacetamide,acetamide, tetramethyl urea and its cyclic analog, N-methylpyrrolidone,sulfolane and the like. Rather than N,N-dibenzylphenylalaninol as thealdehyde precursor, the phenylalaninol derivatives discussed above canbe used to provide the corresponding N-monosubstituted [either P¹ orP²=H] or N,N-disubstituted aldehyde.

In addition, hydride reduction of an amide or ester derivative of thecorresponding alkyl, benzyl or cycloalkenyl nitrogen protectedphenylalanine, substituted phenylalanine or cycloalkyl analog ofphenyalanine derivative can be carried out to provide the aldehydes.Hydride transfer is an additional method of aldehyde synthesis underconditions where aldehyde condensations are avoided, cf, OppenauerOxidation.

The aldehydes of this process can also be prepared by methods ofreducing protected phenylalanine and phenylalanine analogs or theiramide or ester derivatives by, e.g., sodium amalgam with HCl in ethanolor lithium or sodium or potassium or calcium in ammonia. The reactiontemperature may be from about −20° C. to about 45° C., and Preferablyfrom abut 50° C. to about 25° C. Two additional methods of obtaining thenitrogen protected aldehyde include oxidation of the correspondingalcohol with bleach in the presence of a catalytic amount of2,2,6,6-tetramethyl-1-pyridyloxy free radical. In a second method,oxidation of the alcohol to the aldehyde is accomplished by a catalyticamount of tetrapropylammonium perruthenate in the presence ofN-methylmorpholine-N-oxide.

Alternatively, an acid chloride derivative of a protected phenylalanineor phenylalanine derivative as, disclosed above can be reduced withhydrogen and a catalyst such as Pd on barium carbonate or bariumsulphate, with or without an additional catalyst moderating agent suchas sulfur or a thiol (Rosenmund Reduction).

The aldehyde resulting from the Swern oxidation is then reacted with ahalomethyllithium reagent, which reagent is generated in situ byreacting an alkyllithium or arylithium compound with a dihalomethanerepresented by the formula X¹CH₂X² wherein X¹ and X² independentlyrepresent I, Br or Cl. For example, a solution of the aldehyde andchloroiodomethane in THF is cooled to −78° C. and a solution ofn-butyllithium in hexane is added. The resulting product is a mixture ofdiastereomers of the corresponding amino-protected epoxides of theformulas:

The diastereomers can be separated e.g., by chromatography, or,alternatively, once reacted in subsequent steps the diastereomericproducts can be separated. For compounds having the (S) stereochemistry,a D-amino acid can be utilized in place of the L-amino acid.

The addition of chloromethylithium or bromomethylithium to a chiralamino aldehyde is highly diastereoselective. Preferably, thechloromethyllithium or bromomethylithium is generated in-situ from thereaction of the dihalomethane and n-butyllithium. Acceptablemethyleneating halomethanes include chloroiodomethane,bromochloromethane, dibromomethane, diiodomethane, bromofluoromethaneand the like. The sulfonate ester of the addition product of, forexample, hydrogen bromide to formaldehyde is also a methyleneatingagent. Tetrahydrofuran is the preferred solvent, however alternativesolvents such as toluene, dimethoxyethane, ethylene dichloride,methylene chloride can be used as pure solvents or as a mixture. Dipolaraprotic solvents such as acetonitrile, DMF, N-methylpyrrolidone areuseful as solvents or as part of a solvent mixture. The reaction can becarried out under an inert atmosphere such as nitrogen or argon. Forn-butyl lithium can be substituted other organometalic reagents reagentssuch as methyllithium, tert-butyl lithium, sec-butyl lithium,phenyllithium, phenyl sodium and the like. The reaction can be carriedout at temperatures of between about −80° C. to 0° C. but preferablybetween about −80° C. to −20° C. The most preferred reactiontemperatures are between −40° C. to −15° C. Reagents can be added singlybut multiple additions are preferred in certain conditions. Thepreferred pressure of the reaction is atmospheric however a positivepressure is valuable under certain conditions such as a high humidityenvironment.

Alternative methods of conversion to the epoxides of this inventioninclude substitution of other charged methylenation precurser speciesfollowed by their treatment with base to form the analogous anion.Examples of these species include trimethylsulfoxonium tosylate ortriflate, tetramethylammonium halide, methyldiphenylsulfoxonium halidewherein halide is chloride, bromide or iodide.

The conversion of the aldehydes of this invention into their epoxidederivative can also be carried out in multiple steps. For example, theaddition of the anion of thioanisole prepared from, for example, a butylor aryl lithium reagent, to the protected aminoaldehyde, oxidation ofthe resulting protected aminosulfide alcohol with well known oxidizingagents such as hydrogen peroxide, tert-butyl hypochlorite, bleach orsodium periodate to give a sulfoxide. Alkylation of the sulfoxide with,for example, methyl iodide or bromide, methyl tosylate, methyl mesylate,methyl triflate, ethyl bromide, isopropyl bromide, benzyl chloride orthe like, in the presence of an organic or inorganic base.Alternatively, the protected aminosulfide alcohol can be alkylated with,for example, the alkylating agents above, to provide a sulfonium saltsthat are subsequently converted into the subject epoxides withtert-amine or mineral bases.

The desired epoxides formed, using most preferred conditions,diastereoselectively in ratio amounts of at least about an 85:15 ratio(S:R). The product can be purified by chromatography to give thediastereomerically and enantiomerically pure product but it is moreconveniently used directly without purification to prepare retroviralprotease inhibitors. The foregoing process is applicable to mixtures ofoptical isomers as well as resolved compounds. If a particular opticalisomer is desired, it can be selected by the choice of startingmaterial, e.g., L-phenylalanine, D-phenylalanine, L-phenylalaninol,D-phenylalaninol, D-hexahydrophenylalaninol and the like, or resolutioncan occur at intermediate or final steps. Chiral auxiliaries such as oneor two equivilants of camphor sulfonic acid, citric acid, camphoricacid, 2-methoxyphenylacetic acid and the like can be used to form salts,esters or amides of the compounds of this invention. These compounds orderivatives can be crystallized or separated chromatographically usingeither a chiral or achiral column as is well known to those skilled inthe art.

The amino epoxide is then reacted, in a suitable solvent system, with anequal amount, or preferably an excess of, a desired amine of the formulaR³NH₂, wherein R³ is hydrogen or is as defined above. The reaction canbe conducted over a wide range of temperatures, e.g., from about 10° C.to about 100° C., but is preferably, but not necessarily, conducted at atemperature at which the solvent begins to reflux. Suitable solventsystems include protic, non-protic and dipolar aprotic organic solventssuch as, for example, those wherein the solvent is an alcohol, such asmethanol, ethanol, isopropanol, and the like, ethers such astetrahydrofuran, dioxane and the like, and toluene,N,N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. Apreferred solvent is isopropanol. Exemplary amines corresponding to theformula R³NH₂ include benzyl amine, isobutylamine, n-butyl amine,isopentyl amine, isoamylamine, cyclohexanemethyl amine, naphthylenemethyl amine and the like. The resulting product is a 3-(N-protectedamino)-3-(R²)-1-(NHR₃)-propan-2-ol derivative (hereinafter referred toas an amino alcohol) can be represented by the formulas:

wherein P, P¹, P², R² and R³ are as described above. Alternatively, ahaloalcohol can be utilized in place of the amino epoxide.

The amino alcohol defined above is then reacted in a suitable solventwith a sulfonyl chloride (R⁴SO₂Cl) or sulfonyl anhydride in the presenceof an acid scavenger. Suitable solvents in which the reaction can beconducted include methylene chloride, tetrahydrofuran. Suitable acidscavengers include triethylamine, pyridine. Preferred sulfonyl chloridesare methanesulfonyl chloride and benzenesulfonyl chloride. The resultingsulfonamide derivative can be represented, depending on the epoxideutilized by the formulas

wherein P, P¹, P², R², R³ and R⁴ are as defined above. Theseintermediates are useful for preparing inhibitor compounds of thepresent invention and are also active inhibitors of retroviralproteases.

The sulfonyl halides of the formula R⁴SO₂X can be prepared by thereaction of a suitable Grignard or alkyl lithium reagent with sulfurylchloride, or sulfur dioxide followed by oxidation with a halogen,preferably chlorine. Also, thiols may be oxidized to sulfonyl chloridesusing chlorine in the presence of water under carefully controlledconditions. Additionally, sulfonic acids may be converted to sulfonylhalides using reagents such as PCl₅, and also to anhydrides usingsuitable dehydrating reagents. The sulfonic acids may in turn beprepared using procedures well known in the art. Such sulfonic acids arealso commercially available. In place of the sulfonyl halides, sulfinylhalides (R⁴SOX) or sulfenyl halides (R⁴SX) can be utilized to preparecompounds wherein the —SO₂— moiety is replaced by an —SO— or —S— moiety,respectively.

Following preparation of the sulfonamide derivative, the aminoprotecting group P or P¹ and P² amino protecting groups are removedunder conditions which will not affect the remaining portion of themolecule. These methods are well known in the art and include acidhydrolysis, hydrogenolysis and the like. A preferred method involvesremoval of the protecting group, e.g., removal of a carbobenzoxy group,by hydrogenolysis utilizing palladium on carbon in a suitable solventsystem such as an alcohol, acetic acid, and the like or mixturesthereof. Where the protecting group is a t-butoxycarbonyl group, it canbe removed utilizing an inorganic or organic acid, e.g., HCl ortrifluoroacetic acid, in a suitable solvent system, e.g., dioxane ormethylene chloride. The resulting product is the amine salt derivative.Following neutralization of the salt, the amine is then reacted with anamino acid or corresponding derivative thereof represented by theformula (PN[CR^(1′)R^(1″)]_(t)CH(R¹)COOH) wherein t, R¹, R^(1′) andR^(1″) are as defined above, to produce the antiviral compounds of thepresent invention having the formula:

wherein t, P, R¹, R^(1′), R^(1″), R², R³ and R⁴ are as defined above.Preferred protecting groups in this instance are a benzyloxycarbonylgroup or a t-butoxycarbonyl group. Where t is O and R¹ is alkyl,alkenyl, alkynyl, cycloalkyl, —CH₂SO₂NH₂, —CH₂CO₂CH₃, —CO₂CH₃, —CONH₂,—CH₂C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂[S(O)CH₃],—C(CH₃)₂[S(O₂)CH₃], or an amino acid side chain, such materials are wellknown and many are commercially available from Sigma-Aldrich.

Where the amine is reacted with a derivative of an amino acid, e.g.,when t=1, so that the amino acid is a β-amino acid, such β-amino acidscan be prepared according to the procedure set forth in a co-owned,copending patent application, U.S. Ser. No. 07/853,561 or the followingprocedures.

Various methods have been proposed for the preparation of chiral β-aminoacids. See, for example, Chemistry and Biochemistry of Amino Acids, Vol.4, Chapter 5, pp. 250-57, B. Weinstein, Ed., Dekker, N.Y. (1975).Furukawa et al, Chem. Pharm. Bull., 25, 1319 (1977), disclose asymmetricsynthesis of β-amino acids by addition of chiral amines to carbon-carbondouble bonds having nitrile or ester groups in the α-position. However,optical purities of the β-amino acids thus produced range from 2 to 19%.Furukawa et al also report that optically active β-amino acids have beenproduced with optical purities ranging from 2 to 28% by reacting chiralSchiff bases with Reformsky reagent. Terentev et al, Dohl. Ahad. NauhSSR, 163,674 (1965) disclose synthesis of β-aminobutyric acids involvingaddition of chiral amines to crotonic acid with optical purities rangingfrom 7-9%.

Brown et al, Tetrahedron Lett., Vol. 28, No. 19, pp 2179-2182 (1987),disclose a method of preparing optically active disubstituted β-aminoacids which involves asymmetric catalytic hydrogenation of N-substitutedα-(aminoalkyl) acrylates. In order to verify the stereochemistry of theproduct, Curtius rearrangement was effected on the monomethyl ester ofoptically enriched RR-anti-2,3-dimethyl-succinic acid and trapping ofthe incipient isocyanate derivative with tertiary alcohol, namely,t-butyl alcohol, to give the corresponding R-enriched β-amino acid.Ninomita et al, Tetrahedron Lett., Vol. 30, 2152-2157 (1975) studied theCurtius rearrangement utilizing benzoic acid, diphenylphosphoryl azideand triethylamine followed by treatment with various alcohols and foundthat t-butyl alcohol gives yields superior to benzyl alcohol, ethanoland phenol.

Utilization of a primary or secondary alcohol to trap an isocyanatederivative of a chiral mono-substituted succinate, and, in particular,in a Curtius rearrangement of a chiral mono-substituted succinate, toproduce chiral β-amino acids significantly increases the overall yield.The resulting carbamate-protected β-amino esters are then saponified toproduce the corresponding carbamate-protected β-amino acids which arethen deprotected to produce β-amino acids possessing the same absoluteconfiguration as naturally-occurring (L)-amino acids. The overallreaction sequence can be shown as follow:

wherein R¹, R^(1′), R^(1″), and P are as defined above and P⁴OH arepreferably represents radicals derived from primary and secondaryalcohols.

This process can also be used in the asymetric synthesis of β-aminoacids represented by the formula:

wherein R¹, R^(1′) and R^(1″) are as defined above. Such compounds areformed by Curtius rearrangement of 2(R)-substituted succinatesrepresented by the formula

wherein R¹, R^(1′), R^(1″) and P3 are as defined above, to afford theisocyanate derivative:

Using 2(S)-substituted succinates, 2(S)-substituted β-amino acids canalso be prepared stereospecifically.

Curtus rearrangement involves pyrolysis of acyol azides

to yield isocyanates (R—N═C═O) which can be subsequently hydrolyzed togive amines. See March, Advanced Organic Chemistry, p. 1005, 2nd ed(1977). As a general rule, Curtius rearrangement is a concerted reactionand therefore proceeds with retention of configuration of the startingmaterials. Determination of specific reaction conditions for effectingCurtius rearrangements of various succinates is within the skill of onein the art familiar with such reactions. In the method of the presentinvention, Curtius rearrangement to afford the desired isocyante ispreferably effected by treating a 2-substituted succinate with oneequivalent of diphenoxyphosphoryl azide (PhO)₂PON₃ and triethylamine toform the acyl azide followed by heating in an inert solvent, such as inwarm toluene, preferably at about 80° C. for about three hours, toafford the isocyante derivative.

Suitable primary and secondary alcohols include those represented by theformula P⁴OH where P⁴ representes substituted and unsubstituted alkyl,cycloalkyl, aralkyl and aryl radicals, as well as suitable equivalentssuch as, for example, silyl radicals. Preferably, the primary andsecondary alcohols are those wherein P⁴ represents substituted andunsubstituted, straight chain as well as branched chain, alkyl radicalshaving from 1 to about 12 carbon atoms, substituted and unsubstitutedcycloalkyl radicals having from 4 to about 7 carbon atoms, andsubstituted and unsubstituted aryl, alkaryl and aralkyl radicals.Examples of such suitable alcohols include benzyl alcohol, isopropylalcohol, 4-methoxybenzyl alcohol, 2-trimethylsilylethanol, fluorenylmethanol and benzhydrol. Preferred alcohols are benzyl alcohol and4-methoxybenzyl alcohol. Other primary and secondary alcohols suitablefor use in the practice of the present invention will be readilyapparent to those skilled in the art.

The ester derivative is then saponified by any one of numerouswell-known procedures, such as by treatment with aqueous lithiumhydroxide/THF (tetrahydrofuran), preferably for three hours at 0° C. Theresultant product is the corresponding carbamate-protected β-aminoacids. These are subsequently deprotected by any one of severalwell-known procedures, such as by acid catalyzed hydrolysis or byhydrogenolysis, to produce the corresponding deprotected β-amino acids.Alternatively, the carbamate-protected β-amino acid can be coupled tothe amine

followed by deprotection and incorporation of R and R′.

The N-protecting group can be subsequently removed, if desired,utilizing the procedures described above, and then reacted with acarboxylate represented by the formula

wherein R is as defined above and L is an appropriate leaving group suchas a halide. Preferably, where R¹ is a side chain of a naturallyoccurring α-amino acid, R is a 2-quinoline carbonyl group derived fromN-hydroxysuccinimide-2-quinoline carboxylate, i.e., L is hydroxysuccinimide. A solution of the free amine (or amine acetate salt) andabout 1.0 equivalent of the carboxylate are mixed in an appropriatesolvent system and optionally treated with up to five equivalents of abase such as, for example, N-methylmorpholine, at about roomtemperature. Appropriate solvent systems include tetrahydrofuran,methylene chloride or N,N-dimethyl formamide, and the like, includingmixtures thereof.

Alternatively, the protected amino alcohol from the epoxide opening canbe further protected at the newly introduced amino group with aprotecting group P′ which is not removed when the first protecting P isremoved. One skilled in the art can choose appropriate combinations of Pand P′. One suitable choice is when P is Cbz and P′ is Boc. Theresulting compound represented by the formula:

can be carried through the remainder of the synthesis to provide acompound of the formula:

and the new protecting group P′ is selectively removed, and followingdeprotection, the resulting amine reacted to form the sulfonamidederivative as described above. This selective deprotection andconversion to the sulfonamide can be accomplished at either the end ofthe synthesis or at any appropriate intermediate step if desired.

The thiocarbonyl compounds of this invention are really prepared bymethods well known to those skilled in the art, for example, bytreatment of a carbonyl compound with Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)which is an article of commerce. Phosphorus pentasulfide may also beused or one can treat an amine of this invention with a pre-formedthiocarbonyl reagent such as thiocarbonylchlorid in the presence ofbase.

In place of the sulfonyl halides, sulfinyl halides (RSOCl) and sulfenylhalides (RSCl) can be utilized to prepare compounds wherein the —SO₂—moiey is replaced by —SO— or —S—, respectively.

It is contemplated that for preparing compounds of the Formulas havingR⁶, the compounds can be prepared following the procedure set forthabove and, prior to coupling the sulfonamide derivative or analogthereof, e.g. coupling to the amino acid PNH(CH₂)_(t)CH(R¹)COOH, carriedthrough a procedure referred to in the art as reductive amination. Thus,a sodium cyanoborohydride and an appropriate aldehyde or ketone can bereacted with the sulfonamide derivative compound or appropriate analogat room temperature in order to reductively aminate any of the compoundsof Formulas I-IV. It is also contemplated that where R³ of the aminoalcohol intermediate is hydrogen, the inhibitor compounds of the presentinvention wherein R³ is alkyl, or other substituents wherein the α-Ccontains at least one hydrogen, can be prepared through reductiveamination of the final product of the reaction between the amino alcoholand the amine or at any other stage of the synthesis for preparing theinhibitor compounds.

Contemplated equivalents of the general formulas set forth above for theantiviral compounds and derivatives as well as the intermediates arecompounds otherwise corresponding thereto and having the same generalproperties, such as tautomers thereof as well as compounds, wherein oneor more of the various R groups are simple variations of thesubstituents as defined therein, e.g., wherein R is a higher alkyl groupthan that indicated. In addition, where a substituent is designated as,or can be, a hydrogen, the exact chemical nature of a substituent whichis other than hydrogen at that position, e.g., a hydrocarbyl radical ora halogen, hydroxy, amino and the like functional group, is not criticalso long as it does not adversely affect the overall activity and/orsynthesis procedure.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable from known starting materials.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

All reagents were used as received without purification. All proton andcarbon NMR spectra were obtained on either a Varian VXR-300 or VXR-400nuclear magnetic resonance spectrometer.

The following Examples 1 through 9 illustrate preparation ofintermediates. These intermediates are useful in preparing the inhibitorcompounds of the present invention as illustrated in Examples 10-16. Inaddition, the intermediates of Examples 2-6 are also retroviral proteaseinhibitors and inhibit, in particular, HIV protease.

EXAMPLE 1A

Preparation ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]-N-isoamylamine

Part A

To a solution of 75.0 g (0.226 mol) ofN-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of807 mL of methanol and 807 mL of tetrahydrofuran at −2° C., was added13.17 g (0.348 mol, 1.54 equiv.) of solid sodium borohydride over onehundred minutes. The solvents were removed under reduced pressure at 40°C. and the residue dissolved in ethyl acetate (approx. 1 L). Thesolution was washed sequentially with 1M potassium hydrogen sulfate,saturated sodium bicarbonate and then saturated sodium chloridesolutions. After drying over anhydrous magnesium sulfate and filtering,the solution was removed under reduced pressure. To the resulting oilwas added hexane (approx. 1 L) and the mixture warmed to 60° C. withswirling. After cooling to room temperature, the solids were collectedand washed with 2 L of hexane. The resulting solid was recrystallizedfrom hot ethyl acetate and hexane to afford 32.3 g (43% yield) ofN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp150-151° C. and M+Li⁺=340.

Part B

To a solution of 6.52 g (0.116 mol, 1.2 equiv.) of potassium hydroxidein 968 mL of absolute ethanol at room temperature, was added 32.3 g(0.097 mol) of N-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol. Afterstirring for fifteen minutes, the solvent was removed under reducedpressure and the solids dissolved in methylene chloride. After washingwith water, drying over magnesium sulfate, filtering and stripping, oneobtains 27.9 g of a white solid. Recrystallization from hot ethylacetate and hexane afforded 22.3 g (77% yield) ofN-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane, mp 102-103°C. and MH⁺298.

Part C

A solution of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (1.00 g, 3.36 mmol) andisoamylamine (4.90 g, 67.2 mmol, 20 equiv.) in 10 mL of isopropylalcohol was heated to reflux for 1.5 hours. The solution was cooled toroom temperature, concentrated in vacuo and then poured into 10 mL ofstirring hexane whereupon the product crystallized from solution. Theproduct was isolated by filtration and air dried to give 1.18 g, 95% ofN=[[3(S)-phenylmethylcarbamoyl)amino-2(R)-hydroxy-4-phenylbutyl]N-[(3-methylbutyl)]aminemp 108.0-109.5° C., MH⁺m/z=371.

EXAMPLE 1B

Preparation of N,N-dibenzyl-3(S)-amino-1,2-(S)-epoxy-4-phenylbutane

Step A

A solution of L-phenylalanine (50.0 g, 0.302 mol), sodium hydroxide(24.2 g, 0.605 mol) and potassium carbonate (83.6 g, 0.605 mol) in water(500 ml) was heated to 97° C. Benzyl bromide (108.5 ml, 0.912 mol) wasthen slowly added (addition time ˜25 min). The mixture was then stirredat 97° C. for 30 minutes. The solution was cooled to room temperatureand extracted with toluene (2×250 ml). The combined organic layers werethen washed with water, brine, dried over magnesium sulfate, filteredand concentrated to give an oil product. The crude product was then usedin the next step without purification.

Step B

The crude benzylated product of the above step was dissolved in toluene(750 ml) and cooled to −55° C. A 1.5 M solution of DIBAL-H in toluene(443.9 ml, 0.666 mol) was then added at a rate to maintain thetemperature between −55° to −50° C. (addition time—1 hour). The mixturewas stirred for 20 minutes at −55° C. The reaction was quenched at −55°C. by the slow addition of methanol (37 ml). The cold solution was thenpoured into cold (5° C.) 1.5 N HCl solution (1.8 L). The precipitatedsolid (approx. 138 g) was filtered off and washed with toluene. Thesolid material was suspended in a mixture of toluene (400 ml) and water(100 ml). The mixture was cooled to 5° C., treated with 2.5 N NaOH (186ml) and then stirred at room temperature until the solid was dissolved.The toluene layer was separated from the aqueous phase and washed withwater and brine, dried over magnesium sulfate, filtered and concentratedto a volume of 75 ml (89 g). Ethyl acetate (25 ml) and hexane (25 ml)were then added to the residue upon which the alcohol product began tocrystallize. After 30 min., an additional 50 ml hexane was added topromote further crystallization. The solid was filtered off and washedwith 50 ml hexane to give approximately 35 g of material. A second cropof material could be isolated by refiltering the mother liquor. Thesolids were combined and recrystallized from ethyl acetate (20 ml) andhexane (30 ml) to give, in 2 crops, approximately 40 g (40% fromL-phenylalanine) of analytically pure alcohol product. The motherliquors were combined and concentrated (34 g). The residue was treatedwith ethyl acetate and hexane which provided an additional 7 g (˜7%yield) of slightly impure solid product. Further optimization in therecovery from the mother liquor is probable.

Alternatively, the alcohol was prepared from L-phenylalaninol.L-phenylalaninol (176.6 g, 1.168 mol) was added to a stirred solution ofpotassium carbonate (484.6 g, 3.506 mol) in 710 mL of water. The mixturewas heated to 65° C. under a nitrogen atmosphere. A solution of benzylbromide (400 g, 2.339 mol) in 3A ethanol (305 mL) was added at a ratethat maintained the temperature between 60-68° C. The biphasic solutionwas stirred at 65° C. for 55 min and then allowed to cool to 10° C. withvigorous stirring. The oily product solidified into small granules. Theproduct was diluted with 2.0 L of tap water and stirred for 5 minutes todissolve the inorganic by products. The product was isolated byfiltration under reduced pressure and washed with water until the pH is7. The crude product obtained was air dried overnite to give a semi-drysolid (407 g) which was recrystallized from 1.1 L of ethylacetate/heptane (1:10 by volume). The product was isolated by filtration(at −8° C.), washed with 1.6 L of cold (−10° C.) ethyl acetate/heptane(1:10 by volume) and air-dried to give 339 g (88% yield) ofβS-2-[Bis(phenylmethyl)amino]benzene-propanol, mp 71.5-73.0° C. Moreproduct can be obtained from the mother liquor if necessary. The otheranalytical characterization was identical to compound prepared asdescribed above.

Step C

A solution of oxalyl chloride (8.4 ml, 0.096 mol) in dichloromethane(240 ml) was cooled to −74° C. A solution of DMSO (12.0 ml, 0.155 mol)in dichloromethane (50 ml) was then slowly added at a rate to maintainthe temperature at −74° C. (addition time ˜1.25 hr). The mixture wasstirred for 5 min. followed by addition of a solution of the alcohol(0.074 mol) in 100 ml of dichloromethane (addition time −20 min., temp.−75° C. to −68° C.). The solution was stirred at −78° C. for 35 minutes.Triethylamine (41.2 ml, 0.295 mol) was then added over 10 min. (temp.−78° to −68° C.) upon which the ammonium salt precipitated. The coldmixture was stirred for 30 min. and then water (225 ml) was added. Thedichloromethane layer was separated from the aqueous phase and washedwith water, brine, dried over magnesium sulfate, filtered andconcentrated. The residue was diluted with ethyl acetate and hexane andthen filtered to further remove the ammonium salt. The filtrate wasconcentrated to give the desired aldehyde product. The aldehyde wascarried on to the next step without purification.

Temperatures higher than −70° C. have been reported in the literaturefor the Swern oxidation. Other Swern modifications and alternatives tothe Swern oxidations are also possible.

Alternatively, the aldehyde was prepared as follows. (200 g, 0.604 mol)was dissolved in triethylamine (300 mL, 2.15 mol). The mixture wascooled to 12° C. and a solution of sulfur trioxide/pyridine complex (380g, 2.39 mol) in DMSO (1.6 L) was added at a rate to maintain thetemperature between 8-17° C. (addition time—1.0 h). The solution wasstirred at ambient temperature under a nitrogen atmosphere for 1.5 hourat which time the reaction was complete by TLC analysis (33% ethylacetate/hexane, silica gel). The reaction mixture was cooled with icewater and quenced with 1.6 L of cold water (10-15° C.) over 45 minutes.The resultant solution was extracted with ethyl acetate (2.0 L), washedwith 5% citric acid (2.0 L), and brine (2.2 L), dried over MgSO₄ (280 g)and filtered. The solvent was removed on a rotary evaporator at 35-40°C. and then dried under vaccuum to give 198.8 g ofαS-[Bis-(phenylmethyl)amino]-benzenepropanaldehyde as a pale yellow oil(99.9%). The crude product obtained was pure enough to be used directlyin the next step without purification. The analytical data of thecompound were consistent with the published literature. [α]_(D)25=−92.9°(c 1.87, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) ∂, 2.94 and 3.15 (ABX-System,2H, J_(AB)=13.9 Hz, J_(AX)=7.3 Hz and J_(BX)=6.2 Hz), 3.56 (t, 1H, 7.1Hz), 3.69 and 3.82 (AB-System, 4H, J_(AB)=13.7 Hz), 7.25 (m, 15 H) and9.72 (s, 1H); HRMS calcd for (M+1) C₂₃H₂₄NO 330.450. found: 330.1836.Anal. Calcd. for C₂₃H₂₃ON: C, 83.86; H, 7.04; N, 4.25. Found: C, 83.64;H, 7.42; N, 4.19. HPLC on chiral stationary phase: (S,S) Pirkle-Whelk-O1 column (250×4.6 mm I.D.), mobile phase: hexane/isopropanol (99.5:0.5,v/v), flow-rate: 1.5 ml/min, detection with UV detector at 210 nm.Retention time of the desired S-isomer: 8.75 min., retention time of theR-enanatiomer 10.62 min.

Step D

A solution of αS-[Bis(phenylmethyl)amino]benzene-propanaldehyde (191.7g, 0.58 mol) and chloroiodomethane (56.4 mL, 0.77 mol) intetrahydrofuran (1.8 L) was cooled to −30 to −35° C. (colder temperaturesuch as −70° C. also worked well but warmer temperatures are morereadily achieved in large scale operations) in a stainless steel reactorunder a nitrogen atmosphere. A solution of n-butyllithium in hexane (1.6M, 365 mL, 0.58 mol) was then added at a rate that maintained thetemperature below −25° C. After addition the mixture was stirred at −30to −35° C. for 10 minutes. More additions of reagents were carried outin the following manner: (1) additional chloroiodomethane (17 mL) wasadded, followed by n-butyllithium (110 mL) at <−25° C. After additionthe mixture was stirred at −30 to −35° C. for 10 minutes. This wasrepeated once. (2) Additional chloroiodomethane (8.5 mL, 0.11 mol) wasadded, followed by n-butyllithium (55 mL, 0.088 mol) at <−25° C. Afteraddition, the mixture was stirred at −30 to −35° C. for 10 minutes. Thiswas repeated 5 times. (3) Additional chloroiodomethane (8.5 mL, 0.11mol) was added, followed by n-butyllithium (37 mL, 0.059 mol) at <−25°C. After addition, the mixture was stirred at −30 to −35° C. for 10minutes. This was repeated once. The external cooling was stopped andthe mixture warmed to ambient temp. over 4 to 16 hours when TLC (silicagel, 20% ethyl acetate/hexane) indicated that the reaction wascompleted. The reaction mixture was cooled to 10° C. and quenched with1452 g of 16% ammonium chloride solution (prepared by dissolving 232 gof ammonium chloride in 1220 mL of water), keeping the temperature below23° C. The mixture was stirred for 10 minutes and the organic andaqueous layers were separated. The aqueous phase was extracted withethyl acetate (2×500 mL). The ethyl acetate layer was combined with thetetrahydrofuran layer. The combined solution was dried over magnesiumsulfate (220 g), filtered and concentrated on a rotary evaporator at 65°C. The brown oil residue was dried at 70° C. in vacuo (0.8 bar) for 1 hto give 222.8 g of crude material. (The crude product weight was >100%.Due to the relative instability of the product on silica gel, the crudeproduct is usually used directly in the next step without purification).The diastereomeric ratio of the crude mixture was determined by protonNMR:(2s)/(2R):86:14. The minor and major epoxide diastereomers werecharacterized in this mixture by tlc analysis (silica gel, 10% ethylacetate/hexane), Rf=0.29 & 0.32, respectively. An analytical sample ofeach of the diastereomers was obtained by purification on silica-gelchromatography (3% ethyl acetate/hexane) and characterized as follows:

N,N,αS-Tris(phenylmethyl)-2S-oxiranemethanamine

¹H NMR (400 MHz, CDCl₃) ∂ 2.49 and 2.51 (AB-System, 1H, J_(AB)=2.82),2.76 and 2.77 (AB-System, 1H, J_(AB)=4.03), 2.83 (m, 2H), 2.99 & 3.03(AB-System, 1H, J_(AB)=10.1 Hz), 3.15 (m, 1H), 3.73 & 3.84 (AB-System,4H, J_(AB)=14.00), 7.21 (m, 15H); ¹³C NMR (400 MHz,CDCl₃) ∂ 139.55,129.45, 128.42, 128.14, 128.09, 126.84, 125.97, 60.32, 54.23, 52.13,45.99, 33.76; HRMS calcd for C₂₄H₂₆NO (M+1) 344.477, found 344.2003.

N,N,αS-Tris(phenylmethyl)-2R-oxiranemethanamine

¹H NMR (300 MHz, CDCl₃) ∂ 2.20 (m, 1H), 2.59 (m, 1H), 2.75 (m, 2H), 2.97(m, 1H), 3.14 (m, 1H), 3.85 (AB-System, 4H), 7.25 (m, 15H). HPLC onchiral stationary phase: Pirkle-Whelk-O 1 column (250×4.6 mm I.D.),mobile phase: hexane/isopropanol (99.5:0.5, v/v), flow-rate: 1.5 ml/min,detection with UV detector at 210 nm. Retention time of(8): 9.38 min.,retention time of enanatiomer of (4): 13.75 min.

Alternatively, a solution of the crude aldehyde 0.074 mol andchloroiodomethane (7.0 ml, 0.096 mol) in tetrahydrofuran (285 ml) wascooled to −78° C., under a nitrogen atmosphere. A 1.6 M solution ofn-butyllithium in hexane (25 ml, 0.040 mol) was then added at a rate tomaintain the temperature at −75° C. (addition time—15 min.). After thefirst addition, additional chloroiodomethane (1.6 ml, 0.022 mol) wasadded again, followed by n-butyllithium (23 ml, 0.037 mol), keeping thetemperature at −75° C. The mixture was stirred for 15 min. Each of thereagents, chloroiodomethane (0.70 ml, 0.010 mol) and n-butyllithium (5ml, 0.008 mol) were added 4 more times over 45 min. at −75° C. Thecooling bath was then removed and the solution warmed to 22° C. over 1.5hr. The mixture was poured into 300 ml of saturated aq. ammoniumchloride solution. The tetrahydrofuran layer was separated. The aqueousphase was extracted with ethyl acetate (1×300 ml). The combined organiclayers were washed with brine, dried over magnesium sulfate, filteredand concentrated to give a brown oil (27.4 g). The product could be usedin the next step without purification. The desired diastereomer can bepurified by recrystallization at a subsequent step. The product couldalso be purified by chromatography.

Alternatively, a solution ofαS-[Bis(phenylmethyl)amino]benzene-propanaldehyde (178.84 g, 0.54 mol)and bromochloromethane (46 mL, 0.71 mol) in tetrahydrofuran (1.8 L) wascooled to −30 to −35° C. (colder temperature such as −70° C. also workedwell but warmer temperatures are more readily achieved in large scaleoperations) in a stainless steel reactor under a nitrogen atmosphere. Asolution of n-butyllithium in hexane (1.6 M, 340 mL, 0.54 mol) was thenadded at a rate that maintained the temperature below −25° C. Afteraddition the mixture was stirred at −30 to −35° C. for 10 minutes. Moreadditions of reagents were carried out in the following manner: (1)additional bromochloromethane (14 mL) was added, followed byn-butyllithium (102 mL) at <−25° C. After addition the mixture wasstirred at −30 to −35° C. for 10 minutes. This was repeated once. (2)Additional bromochloromethane (7 mL, 0.11 mol) was added, followed byn-butyllithium (51 mL, 0.082 mol) at <−25° C. After addition the mixturewas stirred at −30 to −35° C. for 10 minutes. This was repeated 5 times.(3) Additional bromochloromethane (7 mL, 0.11 mol) was added, followedby n-butyllithium (51 mL, 0.082 mol) at <−25° C. After addition themixture was stirred at −30 to −35° C. for 10 minutes. This was repeatedonce. The external cooling was stopped and the mixture warmed to ambienttemp. over 4 to 16 hours when TLC (silica gel, 20% ethyl acetate/hexane)indicated that the reaction was completed. The reaction mixture wascooled to 10° C. and quenched with 1452 g of 16% ammonium chloridesolution (prepared by dissolving 232 g of ammonium chloride in 1220 mLof water), keeping the temperature below 23° C. The mixture was stirredfor 10 minutes and the organic and aqueous layers were separated. Theaqueous phase was extracted with ethyl acetate (2×500 mL). The ethylacetate layer was combined with the tetrahydrofuran layer. The combinedsolution was dried over magnesium sulfate (220 g), filtered andconcentrated on a rotary evaporator at 65° C. The brown oil residue wasdried at 70° C. in vacuo (0.8 bar) for 1 h to give 222.8 g of crudematerial.

EXAMPLE 2

Preparation ofN-[[3S-(phenylmethylcarbamoyl)amino]-2R-hydroxy-4-phenyl]-1-[(2-methylpropyl)amino-2-(1,1-dimethylethoxyl)carbonyl]butane

To a solution of 7.51 g (20.3 mmol) ofN-[[3S-(phenylmethylcarbamoyl)amino]-2R-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)]aminein 67 mL of anhydrous tetrahydrofuran was added 2.25 g (22.3 mmol) oftriethylamine. After cooling to 0° C., 4.4 g (20.3 mmol) ofdi-tert-butyldicarbonate was added and stirring continued at roomtemperature for 21 hours. The volatiles were removed in vacuo, ethylacetate added, then washed with 5% citric acid, saturated sodiumbicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 9.6 g of crude product. Chromatography on silicagel using 30% ethyl acetate/hexane afforded 8.2 g of pureN-[[3S-(phenylmethylcarbamoyl)amino]-2R-hydroxy-4-phenyl]-1-[(2-methylpropyl)amino-2-(1,1-dimethylethoxyl)carbonyl]butane,mass spectum m/e=477 (M+Li).

EXAMPLE 3A

Preparation ofphenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate

To a solution ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]N-isoamylamine(2.0 gm, 5.2 mmol) and triethylamine (723 uL, 5.5 mmol) indichloromethane (20 mL) was added dropwise methanesulfonyl chloride (400uL, 5.2 mmol). The reaction mixture was stirred for 2 hours at roomtemperature, then the dichloromethane solution was concentrated to ca. 5mL and applied to a silica gel column (100 gm). The column was elutedwith chloroform containing 1% ethanol and 1% methanol. The phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamatewas obtained as a white solid Anal. Calcd for C₂₄H₃₄N₂O₅S: C, 62.31; H,7.41; N, 6.06. Found: C, 62.17; H, 7.55; N, 5.97.

EXAMPLE 3B

Preparation ofphenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate

From the reaction ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]N-isoamylamine(1.47 gm, 3.8 mmol), triethylamine (528 uL, 3.8 mmol) andbenzenesulfonyl chloride (483 uL, 3.8 mmol) one obtainsphenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-carbamate.Column chromatography on silica gel eluting with chloroform containing1% ethanol afforded the pure product. Anal. Calcd for C₂₉H₃₆N₂O₅S: C,66.39; H, 6.92; N, 5.34. Found: C, 66.37; H, 6.93; N, 5.26.

EXAMPLE 4

Preparation ofPhenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(n-propanesulfonyl)amino]-1S-(phenylmethyl)proyl]carbamate

To a solution ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]N-isoamylamine(192 mg, 0.5 mmol) and triethylamine (139 uL, 1.0 mmol) indichloromethane (10 mL) was added dropwise trimethylsilyl chloride (63uL, 0.5 mmol). The reaction was allowed to stir for 1 hour at roomtemperature, cooled to 0° C. with an ice bath and then n-propanesulfonylchloride (56 uL, 0.5 mmol) was added dropwise. The reaction mixture wasstirred for 1.5 hours at room temperature, then diluted with ethylacetate (50 mL) and washed sequentially with 1N HCl, water, saturatedsodium bicarbonate solution, and saturated sodium chloride solution (25mL each). The organic solution was dried over magnesium sulfate,filtered and concentrated to an oil. The oil was stirred with methanol(10 mL) for 16 hours, concentrated and the residue chromatographed onsilica gel (50 gm) eluting with 10% ethyl acetate in hexane (450 mL),then with 1:1 ethyl acetate/hexane. Thephenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(n-propanesulfonyl)amino]-1S-(phenylmethyl)propyl]carbamatewas recrystallized from ethyl ether/hexane to afford a white solid Anal.Calcd. for C₂₆H₃₈N₂O₅S: C, 63.64; H, 7.81; N, 5.71. Found: C, 63.09; H,7.74; N, 5.64.

EXAMPLE 5

The procedure described in Example 2 was used to preparephenylmethyl[2S-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate.

To a solution of N[3(S)-benzyloxycarbonylamino-2(S)-hydroxy-4-phenylbutyl]N-isoamylamine(192 mg, 0.5 mmol) and triethylamine (139 uL, 0.55 mmol) indichloromethane (8 mL) was added dropwise methanesulfonyl chloride (39uL, 0.55 mmol). The reaction mixture was stirred for 16 hours at roomtemperature, then the dichloromethane solution was applied to a silicagel column (50 gm). The column was eluted with dichloromethanecontaining 2.5% methanol. Thephenylmethyl[2S-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamatewas obtained as a white solid Anal. Calcd. for C₂₄H₃₄N₂O₅S ⋄ 0.2 H₂O: C,61.83; H, 7.44; N, 6.01. Found: C, 61.62; H, 7.40; N, 5.99.

EXAMPLE 6

Following the procedures of the previous Examples 1-5, the compounds setforth in Tables 1A and 1B were prepared.

TABLE 1A

Entry R³ R⁴  1 isoamyl p-fluorophenyl  2 isoamyl p-nitrophenyl  3isoamyl o-nitrophenyl  4 isoamyl β-naphthyl  5 isoamyl 2-thienyl  6isoamyl benzyl  7 isobutyl p-fluorophenyl  8 p-fluorobenzyl phenyl  94-pyridylmethyl phenyl 10 cyclohexylmethyl phenyl 11 allyl phenyl 12propyl phenyl 13 cyclopropylmethyl phenyl 14 methyl phenyl 15 propargylphenyl 16 isoamyl p-chlorophenyl 17 isoamyl p-methoxyphenyl 18 isoamylm-nitrophenyl 19 isoamyl m-trifluoromethylphenyl 20 isoamylo-methoxycarbonylphenyl 21 isoamyl p-acetamidophenyl 22 isobutyl phenyl23 —CH₂Ph —Ph 24

—Ph 25

—Ph 26

—Ph 27

—Ph 28

—Ph 29 —CH₂CH═CH₂ —Ph 30

—Ph 31

—Ph 32 —CH₂CH₂Ph —Ph 33 —CH₂CH₂CH₂CH₂OH —Ph 34 —CH₂CH₂N(CH₃)₂ —Ph 35

—Ph 36 —CH₃ —Ph 37 —CH₂CH₂CH₂SCH₃ —Ph 38 —CH₂CH₂CH₂S(O)₂CH₃ —Ph 39—CH₂CH₂CH(CH₃)₂

40 —CH₂CH₂CH(CH₃)₂ —CH₂CH₂CH₃ 41 —CH₂CH₂CH(CH₃)₂ —CH₃ 42 —CH₂CH₂CH(CH₃)₂

43 —CH₂CH₂CH(CH₃)₂

44 —CH₂CH₂CH(CH₃)₂

45 —CH₂CH(CH₃)₂

46 —CH₂CH(CH₃)₂

47 —CH₂CH(CH₃)₂

48 —CH₂CH₂CH₃

49 —CH₂CH₂CH₂CH₃

50 —CH₂CH₂CH(CH₃)₂ —CF₃ 51 —CH₂CH(CH₃)₂ —CH₃ 52 —CH₂CH₂CH(CH₃)₂ —CH₂Cl53 —CH₂CH(CH₃)₂

54 —CH₂CH(CH₃)₂

55 —CH₂CH(CH₃)₂ —CH═CH₂ 56 —CH₂—CH)CH₃)(CH₂CH₃)

MASS MEASUREMENT Entry R³ R⁴ MOL FORM CALC FOUND 1

C₂₉H₃₆N₂O₅S 531 (M + Li) 531 2

C₂₉H₃₆N₂O₆S 541 (M + H) 541 3

C₃₀H₃₆N₂O₆S 555.2529 (M + H) 555.2582 4

5

6

C₂₈H₃₃N₂O₅SF 529.2172 (M + H) 521.2976 7

8

C₂₉H₃₆N₂O₅S₂ 563 (M + Li) 563 9

C₂₉H₃₆N₂O₆S₂ 573 (M + H) 573 10 

C₂₉H₃₆N₂O₇S₂ 595 (M + Li) 595

TABLE 1B

Entry R R³ 1

—CH₂Ph 2

—CH₂CH₂CH(CH₃)₂ 3

—CH₂CH(CH₃)₂ 4

—CH₂CH(CH₃)₂ 5

—CH₂CH(CH₃)₂ 6

—CH₂CH(CH₃)₂ 7

—CH₂CH(CH₃)₂ 8

—CH₂CH(CH₃)₂ 9

—CH₂CH₂(CH₃)₂

TABLE 1C

Mass Determination X R⁸ FORMULA Calc Found H

C₂₇H₃₃N₃O₅S 512.2219 (M + H) 521.2267 OCH₃

C₂₈H₃₅N₃O₆S 548.2407 (M + Li) 548.2434 F

C₂₇H₃₂N₃O₅SF 530 (M + H) 530 Cl

C₂₇H₃₂N₃O₅SCl 546 (M + H) 546 NO₂

C₂₇H₃₂N₄O₇S 557 (M + H) 557 OH

C₂₇H₃₃N₃O₆S 528 (M + H) 528 OCH₃

C₂₈H₃₅N₃O₆S 542.2325 (M + H) 542.2362 OCH₃

C₂₈H₃₅N₃O₆S 548.2407 (M + Li) 548.2393 OCH₃

C₂₈H₃₅N₃O₆S 543 (M + H) 543 OCH₃

C₂₉H₃₆O₆N₂S 547.2454 (M + Li) 547.2475 OCH₃ tert-Butyl C₂₆H₃₈N₂O₆S513.2611 (M + Li) 513.2593 OCH₃

C₂₈H₃₅N₃O₇S 564 (M + Li) 564 OCH₃

C₂₈H₃₅N₃O₇S 564 (M + Li) 564

The following Examples 7-9 illustrate preparation of β-amino acidintermediates. These intermediates can be coupled to the intermediatecompounds of Examples 1-6 to produce inhibitor compounds of the presentinvention containing β-amino acids.

EXAMPLE 7 A. Preparation of 4(4-methoxybenzyl)itaconate

A 5 L three-necked round bottomed flask equipped with constant pressureaddition funnel, reflux condenser, nitrogen inlet, and mechanicalstirrer was charged with itaconic anhydride (660.8 g, 5.88 mol) andtoluene (2300 mL). The solution was warmed to reflux and treated with4-methoxybenzyl alcohol (812.4 g, 5.88 mol) dropwise over a 2.6 hperiod. The solution was maintained at reflux for an additional 1.5 hand then the contents were poured into three 2 L erlenmeyer flasks tocrystallize. The solution was allowed to cool to room temperaturewhereupon the desired mono-ester crystallized. The product was isolatedby filtration on a Buchner funnel and air dried to give 850.2 g, 58% ofmaterial with mp 83-85° C., a second crop, 17% was isolated aftercooling of the filtrate in an ice bath. ¹H NMR (CDCl₃) 300 MHz 7.32(d,J=8.7 Hz, 2H), 6.91(d, J=8.7 Hz, 2H), 6.49(s, 1H), 5.85(s, 1H), 5.12(s,2H), 3.83(s, 3H), 3.40(s, 2H).

B. Preparation of Methyl 4(4-methoxybenzyl)icaconate

A 5 L three-necked round bottomed flask equipped with reflux condenser,nitrogen inlet, constant pressure addition funnel and mechanical stirrerwas charged with 4(4-methoxybenzyl)itaconate (453.4 g, 1.81 mol) andtreated with 1,5-diazabicyclo[4.3.0]non-5-ene (275.6 g, 1.81 mol),(DBN), dropwise so that the temperature did not rise above 15° C. Tothis stirring mixture was added a solution of methyl iodide (256.9 g,1.81 mol) in 250 mL of toluene from the dropping funnel over a 45 mperiod. The solution was allowed to warm to room temperature and stirredfor an additional 3.25 h.

The precipitated DBN hydroiodide was removed by filtration, washed withtoluene and the filtrate poured into a separatory funnel. The solutionwas washed with sat. aq. NaHCO₃ (2×500 mL), 0.2N HCl (1×500 mL), andbrine (2×500 mL), dried over anhyd. MgSO₄, filtered, and the solventremoved in vacuo. This gave a clear colorless oil, 450.2 g, 94% whoseNMR was consistent with the assigned structure. ¹H NMR (CDCl₃) 300 MHz7.30(d, J=8.7 Hz, 2H), 6.90(d, J=8.7 Hz, 2H), 6.34(s, 1H), 5.71(s, 1H),5.09(s, 2H), 3.82(s, 3H), 3.73(s, 3H), 3.38(s, 2H). ¹³C NMR (CDCl₃)170.46, 166.47, 159.51, 133.55, 129.97, 128.45, 127.72, 113.77, 66.36,55.12, 51.94, 37.64.

C. Preparation of Methyl 4(4-methoxybenzyl) 2(R)-methylsuccinate

A 500 mL Fisher-Porter bottle was charged with methyl4(4-methoxybenzyl)itaconate (71.1 g, 0.269 mol), rhodium (R,R) DiPAMPcatalyst (204 mg, 0.269 mmol, 0.1 mol %) and degassed methanol (215 mL).The bottle was flushed 5 times with nitrogen and 5 times with hydrogento a final pressure of 40 psig. The hydrogenation commenced immediatelyand after ca. 1 h the uptake began to taper off, after 3 h the hydrogenuptake ceased and the bottle was flushed with nitrogen, opened and thecontents is concentrated on a rotary evaporator to give a brown oil thatwas taken up in boiling iso-octane (ca. 200 mL, this was repeatedtwice), filtered through a pad of celite and the filtrate-concentratedin vacuo to give 66.6 g, 93% of a clear colorless oil, ¹H NMR (CDCl₃ 300MHz 7.30(d, J=8.7 Hz, 2H), 6.91(d, J=8.7 Hz, 2H), 5.08(s, 2H), 3.82(s,3H), 3.67(s, 3H), 2.95(ddq, J=5.7, 7.5, 8.7 Hz, 1H), 2.79(dd, J=8.1,16.5 Hz, 1H1), 2.45(dd, J=5.7, 16.5 Hz, 1H), 1.23 (d, J=7.5 Hz, 3H).

D. Preparation of Methyl 2(R)-methylsuccinate

A 3 L three-necked round-bottomed flask equipped with a nitrogen inlet,mechanical stirrer, reflux condenser and constant pressure additionfunnel was charged with methyl 4(4-methoxybenzyl) 2(R)-methylsuccinate(432.6 g, 1.65 mol) and toluene (1200 mL). The stirrer was started andthe solution treated with trifluoroacetic acid (600 mL) from thedropping funnel over 0.25 h. The solution turned a deep purple color andthe internal temperature rose to 45° C. After stirring for 2.25 h thetemperature was 27° C. and the solution had acquired a pink color. Thesolution was concentrated on a rotary evaporator. The residue wasdiluted with water (2200 mL) and sat. aq. NaHCO₃ (1000 mL). AdditionalNaHCO₃ was added until the acid had been neutralized. The aqueous phasewas extracted with ethyl acetate (2×1000 mL) to remove the by-productsand the aqueous layer was acidified to pH=1.8 with conc. HCl. Thissolution was extracted with ethyl acetate (4×1000 mL), washed withbrine, dried over anhyd. MgSO₄, filtered and concentrated on a rotaryevaporator to give a colorless liquid 251 g, >100% that was vacuumdistilled through a short path apparatus cut 1: bath temperature 120° C.@ >1 mm, bp 25-29° C.; cut 2: bath temperature 140° C. @ 0.5 mm, bp95-108° C., 151 g, [α]_(d) @ 25° C.=+1.38° C.(c=15.475, MeOH),[α]_(d)=+8.48° C. (neat); cut 3: bath temperature 140° C., bp 108° C.,36 g, [α]_(d) @ 25° C.=+1.49° C.(c=15.00, MeOH), [α]_(d) =+8.98° C.(neat). Cuts 2 and 3 were combined to give 189 g, 78% of product, ¹H NMR(CDCl₃) 300 MHz 11.6(brs, 1H), 3.72(s, 3H), 2.92(ddq, J=5.7, 6.9, 8.0Hz, 1H), 2.81(dd, J=8.0, 16.8 Hz, 1H), 2.47(dd, J=5.7, 16.8 Hz, 1H),1.26(d, J=6.9 Hz, 3H).

E. Preparation of Methyl Itaconate

A 50 mL round bottomed flask equipped with reflux condenser, nitrogeninlet and magnetic stir bar was charged with methyl4(4-methoxybenzyl)itaconate (4.00 g, 16 mmol), 12 mL of touluene and 6mL of trifluoroacetic acid. The solution was kept at room temperaturefor 18 hours and then the volatiles were removed in vacuo. The residuewas taken up in ethyl acetate and extracted three times with saturatedaqueous sodium bicarbonate solution. The combined aqueous extract wasacidified to pH=1-with aqueous potassium bisulfate and then extractedthree times with ethyl acetate. The combined ethyl acetate solution waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. The residue wasthen vacuum distilled to give 1.23 g, 75% of pure product, bp 85-87 @0.1 mm. ¹H NMR (CDCl₃) 300 MHz 6.34(s, 1H), 5.73(s, 2H), 3.76(s, 3H),3.38(s, 2H). ¹³C NMR (CDCl₃) 177.03, 166.65, 129.220, 132.99, 52.27,37.46.

F. Curtius Rearrangement of Methyl 2(R)-methylsuccinate: Preparation ofMethyl N-Moz-α-methyl β-alanine

A 5 L four necked round bottomed flask equipped with a nitrogen inlet,reflux condenser, mechanical stirrer, constant pressure addition funnel,and thermometer adapter was charged with methyl 2(R)-methylsuccinate(184.1 g, 1.26 mol), triethylamine (165.6 g, 218 mL, 1.64 mol, 1.3equivalents), and toluene (1063 mL). The solution was warmed to 85° C.and then treated dropwise with a solution of diphenylphosphoryl azide(346.8 g, 1.26 mol) over a period of 1.2 h. The solution was maintainedat that temperature for an additional 1.0 h and then the mixture wastreated with 4-methoxybenzyl alcohol (174.1 g, 1.26 mol) over a 0.33 hperiod from the dropping funnel. The solution was stirred at 88° C. foran additional 2.25 h and then cooled to room temperature. The contentsof the flask were poured into a separatory funnel and washed with sat.aq. NaHCO₃ (2×500 mL), 0.2N HCl (2×500 mL), brine (1×500 mL), dried overanhyd. MgSO₄, filtered, and concentrated in vacuo to give−302.3 g, 85%of the desired product as a slightly brown oil. 1H NMR (CDCl₃) 300 MHz7.32(d, J=8.4 Hz, 2H), 6.91(d, J=8.4 Hz, 2H), 5.2(brm, 1H), 5.05(s, 2H),3.83(s, 3H), 3.70(s, 3H), 3.35(m, 2H), 2.70(m, 2H), 1.20(d, J=7.2 Hz,3H).

G. Hydrolysis of Methyl N-Moz-α-methyl β-alanine: Preparation ofα-methyl β-alanine Hydrochloride

A 5 L three-necked round bottomed flask equipped with a refluxcondenser, nitrogen inlet and mechanical stirrer was charged with methylN-Moz-α-methyl β-alanine (218.6 g, 0.78 mol), glacial acetic acid (975mL) and 12N hydrochloric acid (1960 mL). The solution was then heated toreflux for 3 h. After the solution had cooled to room temperature (ca. 1h) the aqueous phase was decanted from organic residue (polymer) and theaqueous phase concentrated on a rotary evaporator. Upon addition ofacetone to the concentrated residue a slightly yellow solid formed thatwas slurried pith acetone and the white solid was isolated by filtrationon a Buchner funnel. The last traces of acetone were removed byevacuation to give 97.7 g, 90% of pure product, mp 128.5-130.5° C.[α]_(d) @ 25° C.=9.0° C. (c=2.535, Methanol). ¹H NMR (D₂O) 300 MHz3.29(dd, J=8.6, 13.0 Hz, 1H), 3.16(dd, J=5.0, 13.0 m Hz, 1H), 2.94(ddq,J=7.2, 5.0, 8.6 Hz, 1H), 1.30(d,J=7.2 Hz, 3H); ¹³C MMR (D₂O) 180.84,44.56, 40.27, 17.49.

H. Preparation of N-Boc α-Methyl β-Alanine

A solution of a-methyl b-alanine hydrochloride (97.7 g, 0.70 mol) inwater (1050 mL) and dioxane (1050 mL) the pH was adjusted to 8.9 with2.9N NaOH solution. This stirring solution was then treated withdi-tert-butyl pyrocarbonate (183.3 g, 0.84 mol, 1.2 equivalents) all atonce. The pH of the solution was maintained between 8.7 and 9.0 by theperiodic addition of 2.5N NaOH solution. After 2.5 h the pH hadstabilized and the reaction was judged to be complete. The solution wasconcentrated on a rotary evaporator (the temperature was maintained at<40° C.). The excess di-tert-butyl pyrocarbonate was removed byextraction with dichloromethane and then the aqueous solution wasacidified with cold 1N HCl and immediately extracted with ethyl acetate(4×1000 mL). The combined ethyl acetate extract was washed with brine,dried over anhyd. MgSO₄, filtered and concentrated on a rotaryevaporator to give a thick oil 127.3 g, 90% crude yield that was stirredwith n-hexane whereupon crystals of pure product formed, 95.65 g, 67%,mp 76-78° C., [α]_(d) @ 25° C.=−11.8° C. (c=2.4, EtOH). A second cropwas obtained by concentration of the filtrate and dilution with hexane,15.4 g, for a combined yield of 111.05 g, 78%. ¹H NMR (acetone D₆) 300MHz 11.7 (brs, 1H), 6.05 (brs 1H), 3.35 (m, 1H), 3.22 (m, 1H), 2.50 (m,1H), 1.45(s, 9H), 1.19 (d, J=7.3 Hz, 3H); ¹³C NMR (acetone D₆) 177.01,79.28, 44.44, 40.92, 29.08, 15.50. Elemental analysis calc'd. forC₉H₁₇NO₄: C, 53.19, H, 8.42; N, 6.89. Found: C, 53.36; H, 8.46; N, 6.99.

I. Preparation of N-4-Methoxybenzyloxycarbonyl α-Methyl β-Alanine

A solution of N-4-methoxybenzyloxycarbonyl α-methyl β-alanine methylester (2.81 g, 10.0 mmol) in 30 mL of 25% aqueous methanol was treatedwith lithium hydroxide (1.3 equivalents) at room temperature for aperiod of 2 h. The solution was concentrated in vacuo and the residuetaken up in a mixture of water and ether and the phases separated andthe organic-phase discarded. The aqueous phase was acidified withaqueous potassium hydrogen sulfate to pH=1.5 and then extracted threetimes with ether. The combined ethereal phase was washed with saturatedaqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to give 2.60 g, 97% ofN-4-Methoxybenzyloxycarbonyl α-methyl β-alanine (N-Moz-AMBA) which waspurified by recrystallization from a mixture of ethyl acetate and hexaneto give 2.44 g, 91% of pure product, mp 96-97° C., MH+=268. ¹H NMR(D₆-acetone/300 MHz) 1.16 (3H, d, J=7.2Hz), 2.70 (1H, m), 3.31 (2H, m),3.31 (3H, s), 4.99 (2H, s), 6.92 (2H, 4, J=8.7 Hz), 7.13 (2H, d, J=8.7Hz).

EXAMPLE 8

Utilizing generally the procedure set forth in Example 7, the followingβ-amino acid compounds were prepared.

EXAMPLE 9

Following generally the procedure of Example 7, the β-amino acids setforth in Table 2 were prepared.

TABLE 2

Entry R¹ R^(1′) R^(1″)  1 —CH₃ H H  2 —CH(CH₃)₂ H H  3 —C(CH₃)₃ H H  4 HH H  5 H —CH₃ H  6 H —CH₃ —CH₃  7 H H —CO2CH₃  8 H H —CONH₂  9 —CH₂CH₃ HH 10 —CH₂CH(CH₃)₂ H H 11 —CH₂C₆H₅ H H 12

H H 13

H H 14 —CH₂COOH H H 15 H —CH(CH₃)₂ H 16 H —CH₂CH(CH₃)₂ H 17 H

H 18 H

H 19 H

H 20 H

H 21 H —(CH₂)₃CH(C₆H₅)₂ H

EXAMPLE 10A

Preparation of 4-Pyridinecarboxamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]

To a solution of 231 mg (0.57 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminein 3 mL of methylene chloride at 0 C., was added 288 mg (2.85 mmol) oftriethylamine and then 112 mg (0.63 mmol) of isonicotinoyl chloridehydrochloride. After 19 hours at room temperature, the solvent wasremoved, ethyl acetate added, then washed with saturated sodiumbicarbonate, brine, dried with magnesium sulfate, filtered andconcentrated to afford 290 mg of crude product. This was chromatographedon silica gel using 3-5% isopropanol/methylene chloride as eluent toafford 190 mg of the desired compound; mass spectrum calc. forC₂₇H₃₄N₃O₅S (M+H) 512.2219; -found 512.2280.

EXAMPLE 10B

Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2,6-dimethyl

To a solution of 83 mg (0.55 mmol) of 2,6-dimethylbenzoic acid and 125mg (0.82 mmol) of N-hydroxybenzotriazole in 3 mL of anhydrous DMF at 0C. was added 117 mg (0.61 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. After 2hours at 0 C., 203 mg (0.50 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After 22 hours at room temperature, the solvent was removedin vacuo, ethyl acetate added, then washed with saturated sodiumbicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 300 mg of crude product. Chromatography on silicagel using 20-50% ethyl acetate/hexane afforded 37 mg of the desiredproduct; mass spectrum calcd for C₃₀H₃₈N₂O₅S (M+H) 539.2580; found539.2632.

EXAMPLE 10C

Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl

Part A

Preparation of 4-Nitro-2-methylbenzoic Acid

A mixture of 1.0 g (3.8 mmol) of 2-iodo-nitrotoluene, 2.1 g (15.2 mmol)potassium carbonate and 27 mg (0.038 mmol) of palladium(II) dichloridebis(triphenylphosphine) in a mixture of 5 mL of water and 10 mL ofN,N-dimethylformamide. This was placed in a Fisher/Porter bottle under15 psig of carbon monoxideand heated at 70° C. for 16 hours. Thesolution became homogeneous when heated. The reaction was cooled,diethyl ether and water was added, the organic layer separated anddiscarded. The aqueous layer was acidified with 1N hydrohloric acid,extracted with ethyl acetate, washed with water, brine, dried overmagnesium sulfate, filtered and concentrated to yield 0.5 g of crudematerial. This dissolved in ethyl acetate, hexane added and theresulting brown solid discarded. The filtrate was concentrated, and thenrecrystallized fom diethyl ether/hexane to afford 215 mg of4-nitro-2-methylbenzoic acid, m/e=182(M+H).

Part B

Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-nitro

To a solution of 181 mg (1.0 mmol) of 4-nitro-2-methylbenzoic acid and230 mg (1.5 mmol) N-hydroxybenzotriazole in 3 mL of anhydrousN,N-dimethylformamide at 0° C., was added 211 mg (1.1 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Afterstirring at 0 C. for 1 hour, 406 mg (1 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After 17 hours at room temperature, the solvent was removedunder reduced pressure, ethyl acetate added, washed with 5% citric acid,saturated sodium bicarbonate, brine, dried with magnesium sulfate,filtered and concentrated to yield 0.55 g of crude product. This waschromatographed on silica gel using 20-50% ethyl acetate/hexane aseluent to afford 0.49 g of the desired benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-nitro,m/e=570(M+H).

Part C

Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino)-1S-(phenylmethyl)propyl]-2-methyl-4-amino

A solution of 400 mg (0.70 mmol) of benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-nitrofrom part B in 20 mL of methanol was hydrogenated over 0.2 g of 10%palladium on carbon catalyst under 50 psig of hydrogen for 2.5 hours.The catalyst was removed by filtration and the solution concentrated toafford 370 mg of the desired benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-amino,m/e=540(M+H).

Part D

Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-dimethylamino

A solution of 0.17 g (0.31 mmol) of benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-aminofrom part C in 5 mL of methanol and 0.20 mL of 37% aqueous formaldehydewas hydrogenated over 90 mg of 10% palladium on carbon under 15 psig ofhydrogen for 16 hours. The catalyst was removed by filtration, thesolvents removed under reduced pressure to afford 0.16 g of crudematerial. Chromatography on silica gel using 50% ethyl acetate as eluentafforded 0.12 g of the desired benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl-4-dimethylamino,m/e=568(M+H).

EXAMPLE 10D

Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl

To a solution of 500 mg (1 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminein 2 mL of methylene chloride and 2 mL of N,N-dimethylformamide, wasadded 0.42 mL of triethylamine, followed by 0.12 mL of ortho-toluoylchloride. After 17 hours, the solvent was removed under reducedpressure, the residue dissolved in ethyl acetate, was with 5% citricacid, saturated sodium bicarbonate and brine, dried over anhydrousmagnesium sulfate, filtered and concentrated to afford 490 mg of crudematerial. This was chromatographed over-100 g of silica gel using 20-50%ethyl acetate/hexane as eluent to afford 232 mg of the desired product,m/e=511(M+H).

EXAMPLE 10E

Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-hydroxy-2-methyl

To a solution of 131 mg (0.86 mmol) of 3-hydroxy-2-methylbenzoic acidand 305 mg (0.75 mmol) of N-hydroxybenzotriazole in 4 mL of anhydrousN,N-dimethylformamide at 0° C., was added 165 mg (0.86 mmol) of EDC.After 20 minutes of activation at 0° C. and 1 hour at room temperature,305 mg (0.75 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After 15 hours at room temperature, ethyl acetate was added,washed with 5% citric acid, saturated sodium bicarbonate, brine, dried,filtered and concentrated to afford 460 mg of crude material. This waschromatographed on silica gel using 0-35% ethyl acetate/methylenechloride as eluent to afford 250 mg of pure benzamide,N-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-hydroxy-2-methyl,m/e=547(M+Li).

EXAMPLE 10F

Preparation ofN-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-(2,6-dimethylphenoxy)acetamide

Part A

Preparation of 2,6-Dimethylphenoxyacetic acid

2,6-Dimethylphenol (6.1 g, 50.0 mmol), bromoacetic acid (6.9 g, 50.0mmol) and 2.5 N aqueous sodium hyroxide (50.0 mL, 125.0 mmol) wererefluxed in water (125 mL) for 4 hrs. Bromoacetic acid (6.9 g, 50.0mmol) and 2.5 N aqueous sodium hydroxide (20.0 mL, 62.5 mmol) were addedand the solution refluxed for an additional 16 hrs. The solution wascooled to room temperature and water (200 mL) was added. The pH of thesolution was adjusted to 1.0 with concentrated aqueous hydrochloricacid. The resulting precipitate was collected and recrystallized fromethyl acetate/hexanes (1:9, 700 mL). 2,6-Dimethylphenoxyacetic acid(4.53 g, 25.1 mmol, 50%) was collected as a white crystalline solid. ¹HNMR (CD₃OD) d 2.26 (s, 6H), 4.38 (s, 2H), 6.90-7.00 (m, 3H).

Part B

Preparation ofN-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-(2,6-dimethylphenoxy)acetamide

To a solution of 180.1 mg (0.83 mmol) of 2,6-(dimethylphenoxy)aceticacid in 10 mL of anhydrous methylene chloride at room temperature, wasadded 114 mg (0.60 mmol) of EDC. After 15 minutes of activation, 203 mgof 2R-hydroxy-3-[[(2-methylpropyl)(4-methoxybenzene)sulfonyl]amino]-1S-(phenylmethyl)propylamine was added. After stirringat room temperature for 16 hours the solution was extracted with 5%citric acid, sodium bicarbonate, brine, dried over magnesium sulfate,filtered and concentrated to afford 244 mg of crude product. A quantityof this (15 mg) was chromatographed on silica gel using 25% ethylacetate/hexane to afford 8 mg of the desired compound, m/e=575(M+Li).

EXAMPLE 10G

Preparation ofN-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-(2-methylphenoxy)acetamide

Part A

Preparation of 2-Methylphenoxyacetic Acid

2-Methylphenol (2.0 g, 18.4 mmol), bromoacetic acid (2.5 g, 18.4 mmol)and 2.5 N aqueous sodium hyroxide (25.0 mL, 62.55.0 mmol) refluxed for16 hrs. The pH of the solution was adjusted to 1 with concentratedaqueous hydrochloric acid. The resulting precipitate was collectedtriturated with hexanes. The 2-methylphenoxyacetic acid (720 mg, 4.33mmol, 25%) was collected as a white crystalline solid. ¹HNMR (CD₃₀D) d2.43 (s, 3H), 4.65 (s, 2H) 6.70-7.10 (m, 4H).

Part B

Preparation ofN-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-(2-methylphenoxy)acetamide

To a solution of 9.7 mg (0.59 mmol) of 2-(methylphenoxy) acetic acid in5 mL of anhydrous methylene chloride at room temperature, was added 89.1mg (0.55 mmol) of carbonyl diimidazole. After 15 minutes of activation,200 mg (0.49 mmol) of2R-hydroxy-3-[[(2-methylpropyl)(4-methoxybenzene)sulfonyl]amino]-1S-(phenylmethyl)propylaminewas added. After stirring at room temperature for 15 hours the solutionwas extracted with 5% citric acid, sodium bicarbonate, brine, dried overmagnesium sulfate, filtered and concentrated to afford crude product.This was chromatographed on silica gel using 25% ethyl acetate/hexane toafford 198 mg of the desired compound.

EXAMPLE 10H

Preparation ofN-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-(2,6-dimethylphenylamino)acetamide

Part A

Preparation of N-(2,6 Dimethylphenyl)glycine

2,6-Dimethylaniline (6.1 g, 50.4 mmol), and ethyl bromoacetate (8.4 g,50.4 mmol) were refluxed neat for 10 min. The reaction mixture wascooled to room temperature and poured into dichloromethane (75 mL). Aprecipitated formed which was collected and triturated withdichloromethane (25 mL). N-(2,6-Dimethylphenyl)glycine hydrobromide salt(1.21 g, 4.6 mmol, 9.0%) was collected as a white crystalline solid. ¹HNMR (CD₃OD) d 2.48 (s, 6H), 4.29 (s, 2H), 7.00-7.10 (m, 3H).

Part B

Preparation ofN-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-(2,6-dimethylphenylamino)acetamide

To a solution of 100 mg (0.39 mmol) of N-(2,6-dimethylphenyl)glycinehydrobromide and 100 mg of triethylamine in 5 mL of anhydrous methylenechloride at room temperature, was added 74 mg (0.39 mmol) of EDC. After15 minutes of activation, 157 mg (0.39 mmol) of2R-hydroxy-3-[[(2-methylpropyl)(4-methoxybenzene)sulfonyl]amino]-1S-(phenylmethyl)propylaminewas added. After stirring at room temperature for 4 hours, an additional100 mg of N-(2,6-dimethylphenyl)glycine and 74 mg of EDC was added.After stirring at room temperature for 16 hours, the solution wasextracted with 5% citric acid, sodium bicarbonate, brine, dried overmagnesium sulfate, filtered and concentrated to afford 206 mg of crudeproduct. This was purified by chromtaograpghy on reverse phase using20-90% acetonitrile/water (0.05% trifluoroacetic acid) to afford 75 mgof the desired compound, m/e=568 (M+H).

EXAMPLE 10I

Preparation ofN-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-amino-benzothiazole-6-carboxamide

Part A

Preparation of 2-Amino-6-Carboxy-Benzothiazole Ethyl Ester

A 100 ml round bottom flask equipped with magnetic stir bar and N₂ inletwas charged with 1.0 g of methyl p-aminobenzoate in 35 mL methanol. Thesolution was heated to reflux and 4.0 g of Cu^(II)SO₄ and 5.0 g of KSCNwere added. The reaction mixture was refluxed 2 hours and then filtered.The filtrate was diluted with 60 mL of water and 20 mL of ethanol andheated to boiling. Upon cooling 1.15 g (78%) of2-Amino-6-Carboxy-Benzothiazole Ethyl Ester was isolated, m/e=223(M+H).

Part B

Preparation of 2-Amino-6-Carboxy-Benzothiazole

A 50 mL round bottom flask equipped with magnetic stir bar was chargedwith 250 mg 2-Amino-6-Carboxy-Benzothiazole Ethyl Ester, 190 mg (4 eq.)LiOH in 3 mL dioxane and 3 mL water. The slurry was heated to 60° C. for2 hours. After 2 hours the solution was acidified with 1N HCl andconcentrated in vacuo to a light grey solid which was identified as2-amino-6-carboxy-benzothiazole, m/e=195(M+H). It was used withoutfurther purification.

Part C

Preparation ofN-[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-amino-benzothiazole-6-carboxamide

A 100 mL round bottom flask equipped with magnetic stir bar and N₂ inletwas charged with 110 mg 2-amino-6-carboxybenzothiazole, 110 mg EDC, and100 mg HOBT in 4 mL dry DMF. After 30 minutes activation 203 mg amine(A) and 0.5 mL of triethylamine were added and the reaction was stirredovernight. The reaction was partioned between ethyl acetate andsaturated aqueous sodium bicarbonate. The combined organics were washedwith 10% aqueous Citric Aacid, water, saturated aqueous sodiumbicarbonate, brine and concentrated in vacuo to 210 mg white foam,idenitifed as the desired product, m/e=589(M+Li)

EXAMPLE 11A

Preparation ofN1-[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)amino]butanediamide

Part A

A solution ofphenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)-propyl]carbamateprepared as in Example 3 (100 mg) in methanol (10 mL) was hydrogenatedover 10% palladium on carbon for 2 hours, filtered through diatomaceousearth and concentrated to give the product as an oil.

Part B

A solution of N-CBZ-L-asparagine (61 mg, 0.23 mmol) andN-hydroxybenzotriazole (33 mg, 0.22 mmol) in DMF (2 mL) was cooled to 0°C. with an ice bath and then EDC (42 mg, 0.22 mmol) was added. Thesolution was stirred for 30 minutes at 0° C. and then the product ofPart A (69 mg, 0.21 mmol) in DMF (2 mL) was added. After 30 minutes at0° C. the reaction was allowed to warm to room temperature and stir for˜16 hours. The reaction mixture was then poured into a 50% saturatedaqueous solution of sodium bicarbonate (100 mL) and the resulting whiteprecipitate collected by suction filtration, washed with water and driedin vacuo. Thephenylmethyl[3-amino-1S-([2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino)-1S-(phenylmethyl)amino]carbonyl]-3-oxopropyl]carbamatewas obtained as a white solid Anal. Calcd. for C₂₈H₄₀N₄O₇S.0.5 H₂O: C,57.42; H, 7.06; N, 9.57. Found: C, 57.72; H, 7.21; N, 9.24.

Part C

A solution ofphenylmethyl[3-amino-1S-[[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino)-1S-(phenylmethyl)amino]carbonyl]-3-oxopropyl]carbamate(135 mg, 0.23 mmol) in methanol (15 mL) was hydrogenated over 10%palladium on carbon for 6 hours, filtered through diatomaceous earth andconcentrated to give the product as an oil.

Part D

To a solution of the product from Part C (101 mg, 0.23 mmol) in DMF (5mL) was added 2-quinoline carboxylic acid N-hydroxysuccinimide ester (67mg, 0.25 mmol). The reaction was stirred at room temperature for 16hours, then poured into a 50% saturated solution of sodium bicarbonate(60 mL). The resulting solid was collected by suction filtration washedwith water and dried in vacuo. TheN1-(2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)-amino]-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)-amino]butanediamidewas obtained as a white solid Anal. Calcd. for C₃₀H₃₉N₅O₆S.0.1 H₂O: C,58.52; H, 6.71; N, 11.37. Found: C, 58.34; H, 6.35; N, 11.13.

EXAMPLE 11B

Preparation ofN1-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)amino]butanediamide

Part A

The CBZ protected compoundphenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate(200 mg, 0.38 mmol) was deprotected by hydrogenation over 10% palladiumon carbon and the resulting product obtained as an oil.

Part B

The free amine from Part A was coupled with N-CBZ-L-asparagine (109 mg,0.41 mmol) in the presence of N-hydroxybenzotriazole (63 mg, 0.41 mmol)and EDC (77 mg, 0.40 mmol) to givephenylmethyl[3-amino-1S-[[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)amino]carbonyl]-3-oxopropyl]carbamateas a white solid. Anal. Calcd. for C₃₃H₄₂N₄O₇S: C, 62.05; H, 6.63; N,8.77. Found: C, 61.86; H, 6.60; N, 8.64.

Part C

The product of Part B (110 mg, 0.17 mmol) was deprotected byhydrogenation over 10% palladium on carbon to give the product as anoil.

Part D

The resulting free amine was coupled with 2-quinoline carboxylic acidN-hydroxysuccinimide ester (45 mg, 0.17 mmol) to giveN1-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino)-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)amino]butanediamideas a white solid. Anal. Calcd. for C₃₅H₄₁N₅O₆S: C, 63.71; H, 6.26; N,10.61. Found: C, 63.59; H, 6.42; N, 10.42.

EXAMPLE 12A

Preparation of2S-[[(dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

Part A

To a solution of N-CBZ-L-tert-leucine (100 mg, 0.38 mmol) andN-hydroxybenzotriazole (52 mg, 0.34 mmol) in DMF (3 mL) was added EDC(65 mg, 0.34 mmol). The solution was stirred for 60 minutes at roomtemperature and then the product of Example 10, Part A (105 mg, 0.32mmol) in DMF (2 mL) was added. The reaction was stirred for 16 hours atroom temperature, then poured into a 50% saturated solution of sodiumbicarbonate (50 mL). The aqueous mixture was extracted twice with ethylacetate (25 mL). The combined ethyl acetate layers were washed withwater (25 mL) and dried over magnesium sulfate. Filtration andconcentration produced an oil which was chromatographed on silica gel(50 gm) eluting with 2.5% methanol in dichloromethane. Thephenylmethyl[1S-[[[2R-hydroxy-3-[(3-methylbutyl)-(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]amino]-carbonyl]-2,2-dimethylpropyl]carbamatewas obtained as a gummy solid Anal. Calcd. for C₃₀H₄₅N₃O₆S ⋄ 2.2 H₂O: C,58.55; H, 8.09; N, 6.83. Found: C, 58.38; H, 7.77; N, 7.10.

Part B

A solution ofphenylmethyl[1S-[[[2R-hydroxy-3-](3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)propyl]amino]carbonyl]-2,2-dimethylpropyl]carbamate(100 mg, 0.17 mmol) in methanol (10 mL) was hydrogenated over 10%palladium on carbon for 2 hours. The reaction was filtered throughdiatomaceous earth and concentrated to an oil.

Part C

N,N-dimethylglycine (20 mg, 0.19 mmol), N-hydroxybenzotriazole (28 mg,0.18 mmol) and EDC (35 mg, 0.18 mmol) were stirred in DMF (4 mL) at roomtemperature for 40 minutes. The product from Part B in DMF (4 mL) wasadded and the reaction mixture stirred for 16 hours, then poured into a50% saturated sodium bicarbonate solution (50 mL). The aqueous mixturewas extracted three times with dichloromethane (30 mL) which in turnwere washed with water (30 mL) and dried over magnesium sulfate.Filtration and concentration afforded an oil. The oil waschromatographed on silica gel (50 gm) eluting initially with 2.5 %methanol in dichloromethane (400 mL) and then with 5% methanol indichloromethane. The2S-[[(dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)-propyl]-3,3-dimethylbutanamidewas obtained as a white solid Anal. Calcd. for C₂₆H₄₆N₄O₅S ⋄ 0.5 CH₂Cl₂:C, 56.04; H, 8.34; N, 9.87. Found: C, 56.06; H, 8.36; N, 9.70.

EXAMPLE 12B

Preparation of2S-[[(dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methyl-butyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

Part A

To a solution of N-CBZ-L-tert-leucine (450 mg, 1.7 mmol) andN-hydroxybenzotriazole (260 mg, 1.7 mmol) in DMF (10 mL) was added EDC(307 mg, 1.6 mmol). The solution was stirred for 60 minutes at roomtemperature and then the product of Example 11, Part A (585 mg, 1.5mmol) in DMF (2 mL) was added. The reaction was stirred for 16 hours atroom temperature, then poured into a 50% saturated solution of sodiumbicarbonate (200 mL). The aqueous mixture was extracted thrice withethyl acetate (50 mL). The combined ethyl acetate layers were washedwith water (50 mL) and saturated NaCl solution (50 mL), then dried overmagnesium sulfate. Filtration and concentration produced an oil whichwas chromatographed on silica gel (50 gm) eluting with 20% ethyl acetatein hexane. Thephenylmethyl[1S-[[[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]amino]carbonyl]-2,2-dimethylpropyl]carbamatewas obtained as a solid Anal. Calcd for C₃₅H₄₇N₃O₆S: C, 65.91; H, 7.43;N, 6.59. Found: C, 65.42; H, 7.24; N, 6.55.

Part B

A solution ofphenylmethyl[1S-[[[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)-amino]-1S-(phenylmethyl)propyl]amino]carbonyl]-2,2-dimethylpropyl]carbamate(200 mg, 0.31 mmol) in methanol (15 mL) was hydrogenated over 10%palladium on carbon for 2 hours. The reaction was filtered throughdiatomaceous earth and concentrated to an oil.

Part C

The resulting free amine from part B (150 mg, 0.3 mmol) was combinedwith diisopropylethylamine (114 uL, 0.33 mmol) in dichloromethane (5mL). To this was added bromoacetyl chloride (27 uL, 0.33 mmol) dropwise.The reaction was stirred for 30 minutes at room temperature, thendiluted with dichloromethane (30 mL) and extracted with 1 N HCl, water,and then saturated NaCl solution (25 mL each). The organic solution wasdried over MgSO₄ and concentrated to a solid. The2S-[[bromoacetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl)-3,3-dimethylbutanamidewas sufficiently pure for use in the next step. This material can alsobe prepared by substituing bromoacetic anhydride for bromoacetylchloride, or one can use chloroacetyl chloride or chloracetic anhydride.

Part D

The product from part C was dissolved in dichloromethane (5 mL) anddiisopropylethylamine (114 uL, 0.66 mmol) and dimethylaminehydrochloride (53 mg, 0.66 mmol) were added. The reaction was stirredfor 18 hours then concentrated under a stream of nitrogen to about 1 mL.The residue was chromatographed on silica gel (50 gm) using 2% methanolin dichloromethane. The2S-[[(dimethylamino)-acetyl]amino]-N-[2R-hydroxy-3-[(3methylbutyl)-(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamidewas obtained as a solid. Anal. Calcd for C₃₁H₄₈N₄O₅S: C, 63.24; H, 8.22;N, 9.52. Found: C, 63.03; H, 8.01; N, 9.40.

EXAMPLE 12C

Preparation of2S-[[(methylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methyl-butyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide

2S-[[bromoacetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamide(103 mg, 0.16 mmol) and 40% aqueous methylamine (42 uL, 0.49 mmol) werecombined in ethanol (2 mL) and stirred at room temperature for 24 hours.The reaction mixture was concentrated to dryness and triturated withether. The solid material was removed by filtration and the filtrateconcentrated to an oil. The oil was chromatographed on silica (50 gm)using 4% methanol in dichloromethane. The2S-[[(methylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino)-1S-(phenylmethyl)propyl]-3,3-dimethylbutanamidewas obtained as a solid. Anal. Calcd for C₃₀H₄₆N₄O₅S: C, 62.69; H, 8.07;N, 9.75. Found: C, 62.38; H, 8.14; N. 9.60.

EXAMPLE 12D

Preparation of Pentanamide,2S-[[(dimethylamino))acetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)phenylsulfonyl)amino]-1S-phenylmethyl)propyl]3S-methyl-

Part A

To a solution the amine product of Example 11, Part A; (2.79 g, 7.1mmol) in 27 mL of dioxane was added (2.3 g, 7.1 mmol) ofN-t-butylcarbonyl-L-isoleucine-N-hydroxysuccinamide ester, and thereaction was stirred under nitrogen atmosphere for 16 hours. Thecontents of the reaction were concentrated in vacuo, and the residuedissolved in ethyl acetate, washed with potassium hydrogen sulfate (5%aqueous), saturated sodium bicarbonate, and saturated sodium chloride.The organic layer was dried over magnesium sulfate, filtered andconcentrated to yield 4.3 grams of crude material which waschromatographed using 3:1 ethyl acetate:hexane to obtain 3.05 g, 72%yield of Pentanamide,2S-[[(1,1-dimethylethoxy)carbonyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3-methyl-.

Part B

(3.05 g, 5.0 mmol) of the product from Part A was dissolved in 20 mL of4N HCl in dioxane and stirred under nitrogen atmosphere for 1.5 hours.The contents were concentrated in vacuo, and chased with diethyl ether.The crude hydrochloride salt was pumped on at 1 mm Hg until dry to yield2.54-g of product as its hydrochloride salt.

Part C

(2.54 g, 5.0 mmol) of amine hydrochloride was dissolved in 50 mL oftetrahydrofuran and to this was added (1.01 g, 10 mmol) of4-methyl-morpholine, at which time a precipitate forms. To thissuspension was added chloroacetic anhydride (0.865 g, 5.0 mmol) andstirred for 40 minutes. The contents were concentrated in vacuo, and theresidue partitioned in ethyl acetate (200 mL) and 5% KHSO₄. The organiclayer was washed with saturated sodium bicarbonate, and saturated sodiumchloride, dried over magnesium sulfate, filtered and concentrated toyield the crude product. Purification by silica gel chromatography usingan eluant of 1:1 ethyl acetate:hexanes yielded 1.89 grams of purechloroacetamide.

Part D

To a solution of chloroacetamide (1.89 g, 3.2 mmol) from Part C, in 25mL of tetrahydrofuran was added 4.0 mL of 50% aqueous dimethylamine andthe solution was stirred for 1 hour. The solution was concentrated invacuo and the residue was dissolved in ethyl acetate and washed withwater. The organic layer was dried over magnesium sulfate, filtered andconcentrated to yield the crude product which was purified bycrystallization from ethyl acetate and isooctane to yield 1.80 g, (88%yield), mp.=121-122 C, HRes. MS. calc. 589.3424, found 589.3405.

EXAMPLE 12E

Preparation of Pentanamide,2S-[[(Methylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-

To a solution of the chloroacetamide of Example 12D, Part C, (2.36 g,4.0 mmol) in tetrahydrofuran (25 mL) was added 3 mL of aqueousmethylamine 40 wt %, and the reaction stirred for 1 hour. The contentswere concentrated and the residue was partitioned between ethyl acetate(100 mL) and water (100 mL). The organic layer was dried over magnesiumsulfate, filtered and concentrated to yield the crude product, which waspurified by recrystallization from ethyl acetate heptane; (M+H)575,HRes.found 575.3267.

EXAMPLE 12F

Preparation of Pentanamide,2S-[[(dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-](3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-

Part A

To a solution of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propylamine(1.70 g, 4.18 mmol) in 40 mL of dichloromethane was addedN-carbobenzyloxy-L-isoleucine-N-hydroxysuccinamide ester (1.51 g, 4.18mmol) and the solution stirred under nitrogen atmosphere for 16 hours.The contents were concentrated in vacuo and the residue was redissolvedin ethyl acetate. The ethyl acetate solution was washed with an aqueoussolution of 5% KHSO₄, saturated sodium bicarbonate, and saturated sodiumchloride, dried over magnesium sulfate, filtered, and concentrated toyield 2.47 g of crude product. The product was purified by silica gelchromatography using 1 2:1 hexane:ethyl acetate eluant to yield 2.3 g.(84% yield) of2S-[(carbobenzyloxy)amino]-N-[2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamide.

Part B

(1.18 g, 1.8 mmol) of the product from Part A was dissolved in 50 mL ofmethanol, and to this was added 250 mg of 10% Palladium on Carbon whileunder a stream of nitrogen. The suspension was-hydrogenated using 50psig of hydrogen for 20 hours. The contents were purged with nitrogenand filtered through celite, and concentrated in vacuo to yield 935 mgof2S-(amino)-N-[2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamide,which was used without further purification.

Part C

(0.935 g, 1.8 mmol) of the amine from Part B was dissolved in 15 mL ofdioxane and to this was added (190 mg, 1.85 mmol) of 4-methylmorpholinefolowed by (0.315 g, 1.8 mmol) of chloroacetic anhydride. The reactionmixture was stirred under nitrogen atmosphere for 3 hours, concentratedin vacuo, and redissolved in ethyl acetate. The ethyl acetate solutionwas washed with 50 mL of 5% agueous KHS04, saturated NaHCO₃, andsaturated NaCl solution, dried over MgSO₄, filtered and concentrated toyield 613 mg, (68% yield) of2S-(chloroacetyl)amino]-N-[2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methylpentanamide,after purification by silica gel chromatography using 1:1 hexane:ethylacetate.

Part D

To a solution of the chloroacetamide from Part C (673 mg, 1.10 mmol) in20 mL of tetrahydrofuran was added 5 mL of 50 wt % aqueous dimethylamineand the solution was stirred for 1 hour. The reaction was concentratedand the residue was redissolved in 50 mL of ethyl acetate and washedwith 25 mL of water. The ethyl acetate layer was dried over magnesiumsulfate, filtered and concentrated to yield a crude solid which waspurified by silica gel column chromatography using an eluant of 97:3dichloromethane:methanol to proivde 400 mg of Pentanamide,2S-[[(dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methylpropyl)(4-methoxyphenylsulfonyl)amino]-1S-(phenylmethyl)propyl]-3S-methyl-.

EXAMPLE 13A

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-dimethylaminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester

To a solution of 100 mg (0.19 mmol) of carbamic acid,[2R-hydroxy-3-[[(4-fluorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester in 1 mL of pyridine was added 53 μL of triethylamineand 120 μL (p.95 mmol) of 40% aqueous dimethylamine. After heating for24 hours at 100° C., the solution was cooled, ethyl acetate added, thenwashed with 5% citric acid, saturated sodium bicarbonate, dried overmagnesium sulfate, filtered and concentrated. The resulting solid wasrecrystallized from ethyl acetate/hexane to afford 10 mg of the desiredproduct; mass spectrum m/e=540 (M+H).

EXAMPLE 13B

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester

Part A

A solution of N-benzyloxycarbonyl-3S-amino-1,2-S-epoxy-4-phenylbutane(50 g, 0.168 mol) and isobutylamine (246 g, 3.24 mol) in 650 mL ofisopropyl alcohol was refluxed for 1.25 hours. The solution was cooledto room temperature, concentrated in vacuo and then poured into 1 L ofstirring hexane whereupon the product crystallized from solution, wascollected and air dried to give 57.6 g ofN-[3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl]-N-isobutylamine, mp108-109.5° C., mass spectrum m/e=371(M+H).

Part B

The amine from part A (1.11 g, 3.0 mmol) and triethylamine (324 mg, 3.20mmol) in 20 mL of methylene chloride was treated with 715 mg (3.46 mmol)of 4-methoxybenzenesulfonyl chloride. The solution was stirred at roomtemperature for 6 hours, concentrated, dissolved in ethyl acetate, thenwashed with 1N potassium hydrogen sulfate, saturated sodium bicarbonate,brine, dried over magnesium sulfate, filtered and concentrated to afforda clear oil. This was recrystallized from diethyl ether to afford 1.27 gof carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester, mp 97-101° C., mass spectrum m/e=541 (M+H).

Part C

A solution of 930 mg (3.20 mmol) of the product of part B in 30 mL ofmethanol was hydrogenated in the presence of 70 mg of a 10% palladium oncarbon catalyst under 40 psig for 17 hours, the catalyst was removed byfiltration, and the solution concentrated to afford 704 mg of[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine,mass spectrum m/e=407 (M+H), which was used directly in the next stepwithout purification.

Part D

To a solution of 2.5 g (22.9 mmol) of 3-pyridylcarbinol in 100 mL ofanhydrous acetonitrile was added 8.8 g (34.4 mmol) ofN,N′-disuccinimidyl carbonate and 5.55 mL (68.7 mmol) of pyridine. Thesolution was stirred for 1 hour and then concentrated in vacuo. Theresidue was dissolved in ethyl acetate, then washed with saturatedsodium bicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 5.3 g of N-Hydroxysuccinimide-3-pyridylmethylcarbonate, mass spectrum m/e=251 (M+H), which was used directly in thenext step without purification.

Part E

To a solution of the amine from part C (2.87 g, 7.0 mmol) and 1.38 mL oftriethylamine in 24 mL of anhydrous methylene chloride was added asolution of1.65 g (6.6 mmol) of N-hydroxysuccinimide-3-pyridyl carbonatefrom part D in 24 mL of methylene chloride. The solution was stirred for1 hour, 100 mL of methylene chloride added, then washed with saturatedsodium bicarbonate, brine, dried over sodium sulfate, filtered andconcentrated to afford 3.69 g of crude product. Chromatography on silicagel using 2% methanol/methylene chloride to afford 3.27 g of carbamicacid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester, mass spectrum m/e=548 (M+Li).

EXAMPLE 13C

Preparation of Carbamic acid,[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester

Part A

A solution of N-benzyloxycarbonyl-3S-amino-1,2-S-epoxy-4-phenylbutane(50 g, 0.168 mol) and isobutylamine (246 g, 3.24 mol) in 650 mL ofisopropyl alcohol was refluxed for 1.25 hours. The solution was cooledto room temperature, concentrated in Vacuo and then poured into 1 L ofstirring hexane whereupon the product crystallized from solution, wascollected and air dried to give 57.6 g ofN-[3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl]-N-isobutylamine, mp108-109.5 C., mass spectrum m/e=371(M+H).

Part B

The amine from part A (0.94 g, 2.5 mmol) and triethylamine (288 mg,2.85mmol) in 20 mL of methylene chloride was treated with 461 mg(2.61 mmol)of benzenesulfonyl chloride. The solution was stirred at roomtemperature for 16 hours, concentrated, dissolved in ethyl acetate, thenwashed with 1N potassium hydrogen sulfate, saturated sodium bicarbonate,brine, dried over magnesium sulfate, filtered and concentrated to afforda clear oil. This was recrystallized from diethyl ether and hexane toafford 0.73 g of carbamic acid,[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester, mp 95-99 C., mass spectrum m/e=511 (M+H).

Part C

A solution of 500 mg of carbamic acid,[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester in 20 mL of methanol was hydrogenated in the presenceof 250 mg of a 10% palladium on carbon catalyst under 40 psig for 3hours, the catalyst was removed by filtration, and the solutionconcentrated to afford 352 mg of[2R-hydroxy-3-[(phenylsulfonyl])2-methylpropyl)amino]-1S-(phenylmethyl)propylamine,mass spectrum m/e=377 (M+H), which was used directly in the next stepwithout purification.

Part D

To a solution of 1.24 mmol of 5-norbornene-2,3-dicarboximidocarbonochloridate (Henklein, P., et. al., Synthesis 1987, 166-167) in 1mL of anhydrous methylene chloride, was added a solution of 43 μL (2.44mmol) of 3-pyridylcarbinol and 129 μL (1.6 mmol) of pyridine in 1 mL ofmethylene chloride at 0° C. under a nitrogen atmosphere. After 4 hoursat room temperature, 150 mg (0.4 mmol) of[2R-hydroxy-3-((phenylsulfonyl])2-methylpropyl)amino]-1S-(phenylmethyl)propylaminefrom Part C above was added and 100 μL of pyridine. After stirring for15 hours at room temperature, ethyl acetate was added, then washed with1N hydrochloric acid, saturated sodium bicarbonate, brine, dried overmagnesium sulfate, filtered and concentrated to afford 175 mg of crudeproduct. Chromatography over silica gel using 1% methanol/methylenechloride to afford 69 mg of pure carbamic acid,[2R-hydroxy-3-[(phenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester, mass spectrum m/e=512.2267 (M+H); calcd forC₂₇H₃₃N₃O₅S, 512.2219.

EXAMPLE 13D

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester, N-oxide

To a solution of 211 mg (0.39 mmol) of carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester in 5 mL of methylene chloride at 0° C. was added500 mg of 50% 3-chloroperbenzoic acid. After stirring at roomtemperature for 1 hour, ethyl acetate was added, the solution washedwith saturated sodium bicarbonate, 0.2N ammonium hydroxide solution andbrine, dried over magnesium sulfate, filtered and concentrated to afford200 mg of crude product. This was chromatographed on C18 reverse phasematerial using 20-40% acetonitrile/water, then 100% acetonitrile toafford 90 mg of the desired product, which was then recrystallized fromethyl acetate/isooctane to yield 34 mg of pure carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester, N-oxide; mass spectrum m/e=564 (M+Li).

EXAMPLE 13E

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester

Part A

A solution of 0.98 g (1.85 mmol) of carbamic acid,[2R-hydroxy-3-[[(4-fluorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-phenylmethylester in 3.8 mL of anhydrous DMF was added to 22 mg (7.4 mmol) of 80%sodium hydride in 2 mL of DMF. To this mixture was added 0.40 g (3.7mmol) of benzyl alcohol. After 2 hours, the solution was cooled to 0 C.,water added, and then ethyl acetate. The organic layer was washed with5% cirtic acid, saturated sodium bicarbonate and brine, dried overmagnesium sulfate, filtered and concentrated to afford 0.90 g of crudematerial. This was chromatographed on basic alumina using 3%methanol/methylene chloride to afford 0.70 g of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine,cyclic carbamate; mass spectrum m/e=509(M+H).

Part B

To a solution of 0.65 g (1.28 mmol) of the cyclic carbamate from part Ain 15 mL of ethanol, was added 2.6 mL (6.4 mmol) of 2.5N sodiumhydroxide solution. After 1 hour at reflux, 4 mL of water was added andthe solution refluxed for an additional eight hours. The volatiles wereremoved, ethyl acetate added, and washed with water, brine, dried overmagnesium sulfate, filtered and concentrated to afford 550 mg of crude2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine.

Part C

A solution of crude2R-hydroxy-3-[(2-methylpropyl)(4-benzyloxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminein 10 mL of ethanol was hydrogenated in the presence of 500 mg of a 10%palldium on carbon catalyst under 50 psig of hydrogen for 2 hours. Thecatalyst was removed by filtration and the solvent removed in vacuo toafford 330 mg of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine,mass spectrum m/e=393 (M+H).

Part D

To a solution of 320 mg (0.82 mmol) of the amine from part C in 6 mL ofDMF, was added 192 mg (0.76 mmol) ofN-hydroxysuccinimide-3-pyridylmethyl carbonate. After 15 hours at roomtemperature, the DMF was removed in vacuo, ethyl acetate added, washedwith water, brine, dried with magnesium sulfate, filtered andconcentrated to afford 390 mg of crude material. Chromatogrpahy onsilica gel using 50-80% ethyl acetate/hexane afforded 180 mg of carbamicacid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-pyridylmethyl ester, mass spectrum m/e=528(M+H).

EXAMPLE 13F

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-pyrimidylmethyl ester

To a solution of 9.5 mg (0.09 mmol) of 5-pyrimidylcarbinol in 1 mL ofanhydrous acetonitrile at room temperature, was added 24 mg (0.09mmol)of N,N′-disuccinimidyl carbonate and 19.1 μL (0.24 mmol) of pyridine.After stirring for 5 hours, 32 mg (0.08 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added and the solution stirred for 48 hours. After concentration invacuo, methylene chloride was added, then washed with a 1:1 mixture ofsaturated sodium bicarbonate and brine, dried over magnesium sulfate,filtered and concentrated to give 27 mg of crude product. Chromatographyon silica gel using 2% methanol/methylene chloride afforded 22 mg of thedesired product, mass spectrum m/e=543(M+H).

EXAMPLE 13G

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester

Part A

Preparation of Ethyl 6-Aminonicotinate

To a suspension of 1.3 g (9.4 mmol) 6-aminonicotinic acid in 100 mL ofethanol, was bubbled in dry hydrochloric acid at 0° C., then thesolution was refluxed until all the solids dissolved. The solvents wereremoved under reduced pressure, the residue dissolved in ethyl acetate,washed with saturated sodium bicarbonate, brine and concentrated toafford 1.37 g of a white solid, m/e=166(M+H).

Part B

Preparation of Ethyl 6-(tert-Butyloxycarbonylamino)nicotinate

A mixture of 848 mg(5.1 mmol) of ethyl 6-aminonicotinate from part A,1.11 g (5.1 mmol) of di-tert-butylpyrocarbonate and 0.71 mL (5.1 mmol)of triethylamine in 10 mL of anhydrous toluene was refluxed for 15hours. The solution was cooled, ethyl acetate added, washed withsaturated sodium bicarbonate, brine, dried over anhydrous magnesiumsulfate, filtered and concentrated to afford 1.28 g of the desired ethyl6-(tert-butyloxycarbonylamino)nicotinate, m/e=267(M+H), which was useddirectly in the next step.

Part C

Preparation of 6-(tert-Butyloxycarbonylamino)-3-pyridylmethanol

To 4.6 mL (4.6 mmol) of a 1M solution of lithium aluminum hydride indiethyl ether at −40° C. under a nitrogen atmosphere, was added aslution of 618 mg (2.3 mmol) of ethyl6-(tert-butyloxycarbonylamino)nicotinate from part B in 40 mL ofanhydrous tetrahydrofuran. After the addition, this was warmed to roomtemperature, stirred for 3 hours, cooled to 0° C., and 145 μL of water,145 μL of 20% sodium hydroxide solution and 290 μL of water weresuccessively added. To the resulting mixture was added 50 mL oftetrahydrofuran and stirring continued for 30 minutes. Anhydrousmagnesium sulfate was added, the solids removed via filtration and thefiltrate concentrated under reduced pressure to afford 460 mg of thedesired product, m/e=224(M+), which was used directly in the next step.

Part D

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-[(6-tert-butyloxycarbonylamino)pyridyl]methyl ester

To a solution of 336 mg (1.5mmol) of6-(tert-butyloxycarbonylamino)-3-pyridylmethanol from part C in 14 mL ofanhydrous acetonitrile at room temperature under a nitrogen atmosphere,was added 384 mg (1.5mmol) of N,N′-disuccinimidyl carbonate and 364 μL(4.5 mmol) of anhydrous pyridine. After 4 hours, 406 mg (1 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added and stirring continued for 19 hours. The solvent was removedunder reduced pressure, ethyl acetate added, washed with saturatedsodium bicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 702 mg of crude product. Chromatography on silicagel using 1% methanol/methylene chloride as eluent afforded 170 mg ofthe desired carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-[(6-tert-butyloxycarbonylamino)pyridyl]methyl ester, m/e=663(M+Li).

Part E

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester

To 5 mL of 4N hydrochloric acid in dioxane at room temperature, wasadded 150 mg (0.23 mmol) of carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-[(6-tert-butyloxycarbonylamino)pyridyl]methyl ester from part D. Afterstirring at room temperature for 28 hours, the solvent was removed underreduced pressure, the resulting solids triturated with diethyl ether,then dissolved in ethyl acetate and saturated sodium bicarbonateslution, separated, the organic layer washed with brine, dried withmagnesium sulfate, filtered and concentrated. The residue waschromatographed on silica gel using 2.5% methanol/methylene chloride toyield 59 mg of the desired carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester, m/e=557(M+H).

EXAMPLE 13H

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester

Part A

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-[(6-tert-butyloxycarbonylamino)pyridyl]methyl ester

To a solution of 505 mg (2.25mmol) of6-(tert-butyloxycarbonylamino)-3-pyridylmethanol from in 20 mL ofanhydrous acetonitrile at room temperature under a nitrogen atmosphere,was added 576 mg (2.25mmol) of N,N′-disuccinimidyl carbonate and 546 μL(6.75 mmol) of anhydrous pyridine. After 1 hour, 837 mg (1.87 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added and stirring continued for 3 hours. The solvent was removedunder reduced pressure, ethyl acetate added, washed with saturatedsodium bicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 1.37 g of crude product. Chromatography on silicagel using 1% methanol/methylene chloride as eluent afforded 830 mg ofmaterial which was identified as a mixture of the desired carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-[(6-tert-butyloxycarbonylamino)pyridyl]methyl ester and the cycliccarbamate derived from the2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine.The mixture was very difficult to separate, so was used as is in thenext step.

Part B

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester

To 830 mg of the mixture from part A, was added 50 mL of a 1:1 mixtureof trifluoroacetic acid and methylene chloride. After 2.5 hours at roomtemperature, the solvent was removed under reduced pressure, ethylacetate added, washed with saturated sodium bicarbonate, dried overmagnesium sulfate, filtered and concentrated to afford 720 mg of crudematerial. This was chromatgraphed on silica gel using 5% methanol/ethylacetate as eluent to yield 220 mg of product, which was recrystallizedfrom methylene chloride/diethyl ether to afford 108 mg of the desiredcarbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-aminopyridyl)methyl ester, m/e=549(M+Li).

EXAMPLE 13I

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-hydroxypyridyl)methyl ester

Part A

Preparation of tert-Butyldimethylsilyl6-(tert-butyldimethylsiloxy)nicotinate

To a solution of 5.0 g (35.9 mmol) of 6-hydroxynicotinic acid in 200 mLof anhydrous N,N-dimethylformamide at room temperature, was added 8.56 g(125 mmol) of imidazole and then 13.5 g (89 mmol) oftert-butyldimethylsilyl chloride. After 20 hours, the solvent wasremoved under reduced pressure, ethyl acetate added, washed with water,5% citric acid, saturated sodium bicarbonate, brine, dried overanhydrous magnesium sulfate, filtered and concentrated to afford 10.5 gof crude material, m/e=368(M+H).

Part B

Preparation of 3-(6-tert-butyldimethylsiloxy)pyridylcarbinol

To 11 mL of 1M solution of lithium aluminum hydride in diethyl ether at−35° C. under a nitrogen atmosphere, was added a solution of 2.0 g (5.46mmol) of product from part A in 20 mL of anhydrous diethyl ether. After30 minutes, the reaction was warmed to 0° C. and stirred for 40 minutes.The solution was then quenched by the careful addition of 0.42 mL ofwater, 0.42 mL of 20% sodium hydroxide solution, and 0.84 mL of ater.Ethyl acetate was added, the precipate filtered and the organic phaseconcentrated to yield 0.93 g of crude3-(6-tert-butyldimethylsiloxy)pyridylcarbinol, which was used directlyin the next step.

Part C

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-hydroxypyridyl)methyl ester

To a solution of 860 mg (3.6 mmol) of material from part B in 15 mL ofanhydrous acetonitrile, was added 919 mg (3.6 mmol) ofN,N′-disuccinimidyl carbonate and 0.87 mL of pyridine. After 1 hour,1.42 g (3.5 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After 14 hours at room temperature, the solvent was removedunder reduced pressure, the residue disslved in ethyl acetate, washedwith 5% citric acid, saturated sodium bicarbonate, brine, dried overmagnesium sukfate, filtered and concentrated to afford 2.1 g of crudematerial. This was directly deprotected by dissolving in 40 mL of 80%acetic acid/water and stirring for 2 hours. The solvents were removedunder reduced pressure, the residue dissolved in ethyl acetate, washedwith saturated sodium bicarbonate, brine, dried over magnesium sulfate,filtered and concentrated to afford 1.7 g of crude product. This waschromatographed on silica gel using 50-100% ethyl acetate/hexane toprovide a fraction of 0.19 g of fairly pure material, which was furtherpurified by reverse phase chromatography using 15-40% acetonitrile/water(0.05% trifluoroacetic acid) to provide 120 mg of the desired carbamicacid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,3-(6-hydroxypyridyl)methyl ester, m/e=558(M+H).

EXAMPLE 13J

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl],5-pyrimidylmethyl ester

To a solution of 237 mg (2.15 mmol) of 5-pyrimidylcarbinol in 24 mL ofanhydrous acetonitrile , was added 602 mg (2.35 mmol) ofN,N′-disuccinimidyl carbonate and then 0.47 mL of pyridine. Afterstirring for 4.5 hours, 766 mg (1.96 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After stirring for 19 hours, the solvent was removed underreduced pressure, ethyl acetate added, washed with 5% citric acid,saturated sodium bicarbonate, brine, dried over anhydrous magnesiumsulfate, filtered and concentrated to afford 1.0 g of crude material.Chromatography on silica gel using 50-100% ethyl acetate/hexane aseluent afforded 450 mg of the desired carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-pyrimidylmethyl ester, m/e=529(M+H).

EXAMPLE 13K

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl],3-furanylmethyl ester

To a solution of 98 mg (1 mmol) of 3-(hydroxymethyl)furan in 3 mL ofanhydrous acetonitrile, was added 242 μL of pyridine and then 256 mg ofN,N′-disuccinimidyl carbonate at room temperature under nitrogen. After45 minutes, 406 mg (1 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After stirring at room temperature for 16 hours, ethylacetate was added, washed with 5% citric acid, saturated sodiumbicarbonate and brine, dried over magnesium sulfate, filtered andconcentrated to afford 565 mg of crude product. This was chromatographedon silica gel using 50% ethyl acetate/hexane as eluent to afford 305 mgof a white foam, which was recrystallized from diethyl ether/hexane toyield 245 mg of pure carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-furanylmethyl ester, m/e=537(M+Li).

EXAMPLE 14

Preparation ofphenylmethyl[3-amino-1S-[[2R-hydroxy-3-[(3-propyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)amino]-carbonyl]-3-oxopropyl]carbamate

Phenylmethyl[2R-hydroxy-3-[(3-propyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)propyl]carbamate(200 mg, 0.40 mmol) was deprotected by hydrogenation over 10% palladiumon carbon and the resulting free amine was coupled withN-CBZ-L-asparagine (157 mg,0.42 mmol) in the presence ofN-hydroxybenzotriazole (114 mg, 0.84 mmol) and EDC (130 mg, 0.67 mmol)to givephenylmethyl[3-amino-1S-[[2R-hydroxy-3-[(3-propyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)amino]carbonyl]-3-oxopropyl]carbamateas a solid. Anal. Calcd for C₃₁H₃₈N₄O₇S.0.2H₂O: C, 60.61; H, 6.30; N,9.12. Found: C, 60.27; H, 6.16; N, 8.93.

EXAMPLE 15A

Preparation ofN¹-[2R-hydroxy-3-[(3-methylbutyl)(phenyl-sulfonyl)amino]-N⁴-methyl-1S-(phenylmethyl)propyl]-2S-(2-quinolinylcarbonyl)amino]butanediamide

Part A

N²-[(1,1-dimethylethoxy)carbonyl]-N-methyl-L-asparagine was preparedfrom Boc-L-aspartic acid alpha-benzyl ester (1.0 g, 3.09 mmol),methylamine.HCl (209 mg, 3.09 mmol), EDC (711 mg, 3.7 mmol),1-hydroxybenzotriazole (627 mg, 4.63 mmol), and N-methylmorpholine (0.7mL, 6.3 mmol), in DMF (20 mL). After stirring overnight at roomtemperature, the reaction mixture was diluted with ethyl acetate, washedwith water, saturated sodium bicarbonate, 5% citric acid, brine, driedover magnesium sulfate and concentrated to an oil. The oil was taken upin 20 mL dry ethanol, and hydrogenated in the presence of 10% w/w of 10%Pd on C at atmospheric pressure and room temperature overnight. Themixture was filtered through Celite and concentrated to a white solidfoam, 670 mg.

Part B

A solution ofphenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-1S-(phenylmethyl)-propyl]carbamate(310 mg, 0.59 mmol) in methanol (10 mL) was hydrogenated over 10%palladium on carbon for 3 h., filtered through diatomaceous earth andconcentrated to give the product as an oil (214 mg). This free amine(208 mg, 0.53 mmol) was coupled withN2-[(1,1-dimethylethoxy)-carbonyl]-N-methyl-L-asparagine (137 mg, 0.56mmol) in the presence of N-hydroxybenzotriazole (102 mg, 0.76 mmol) andEDC (130 mg, 0.67 mmol) to yield 290 mg ofN1[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)-amino]-N4-methyl-1S-(phenylmethyl)propyl]-2S-[(1,1-dimethylethoxy-carbonyl)amino]butanediamide.

Part C

N¹[2R-hydroxy-3-[(3-methylbutyl)(phenyl-sulfonyl)amino]-N⁴-methyl-1S-(phenylmethyl)propyl]-2S-[(1,1-dimethylethoxycarbonyl)-amino]butanediamide (270 mg, 0.43 mmol) was stirred in 4N HCl in dioxane (5 mL) atroom temperature for 0.5 hr. Solvent and excess reagent were evaporatedto dryness. The product was dried in vacuo. This material (125 mg, 0.225mmol) was then reacted with 2-quinolinecarboxylic acidN-hydroxysuccimide ester (61 mg, 0.225 mmol), N-methylmorpholine (50 uL,0.45 mmol) in methylene chloride (2 mL) for 3 h. The productN¹[2R-hydroxy-3-[(3-methylbutyl)(phenylsulfonyl)amino]-N⁴-methyl-1S-(phenylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)-amino]butanediamidewas purified by silica gel chromatography. Anal. Calcd forC₃₆H₄₃N₅O₆S.0.2H₂O: C, 63.83; H, 6.45; N, 10.34. Found: C, 63.64; H,6.40; N, 10.34.

EXAMPLE 15B

Preparation of Carbamic acid,[3-[[2-hydroxy-3-[(3-methylbutyl)(phenylsufonyl)amino]-1-(phenylmethyl)propyl]amino]-2-methyl-3-oxopropyl]-,(4-methoxyphenyl)methyl ester, [1S-[1R*(S*),2S*]]-

Carbamic acid,[2R-hydroxy-3-[(3-methylbutyl)(phenylsulphonyl)amino]-1S-(phenylmethyl)propyl]-,phenylmethyl ester (4.10 g, 7.8 mmol) was hydrogenated in a solution ofmethanol and ethanol using catalytic Pd/C 10% at 50 psig hydrogen for 3hours. The catalyst was filtered and the solvents removed in vacuo toyield 3.0 grams of free amine. In a separate flask, 2.09 g, (7.8 mmol),of N-Moz-AMBA was added to 10 mL of dimethylformamide and 1.58 g, 11.5equiv.), of N-hydroxybenzoltriazole and the solution was cooled to 5° C.To this solution was added 1.49 g, (7.8 mmol), of EDC and the solutionstirred for 30 min. To this was added the free amine in 10 mL ofdimethylformamide, and the reaction was stirred for 20 hours. Thesolvent was removed by evaporation and the crude material waspartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The ethyl acetate layer was washed with 5% potassiumhydrogen sulfate and brine, dried over magnesium sulfate, filtered andconcentrated to yield 2.58 grams (52%) of pure product afterrecrystallization from ethyl acetate, ether, and hexanes.

EXAMPLE 16A

Preparation of Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,tetrahydrofuran-3S-yl ester

To a solution of 406 mg (1.0 mmol) of[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminein 5.0 mL of dichloromethane containing 150 mg (1.5 mmol) oftriethylamine was added 280 mg (1.22 mmol) ofN-succinimidyl-3S-tetrahydrofuranyl carbonate and the reacton mixturewas stirred for 2 hours, an additonal 136 mg (0.3 mmol) of amine wasadded to the mixture and the solution stirred another 2 hours. Thecontents were diluted with 50 mL of ethyl acetate and washed with 5%aqueous citric acid, saturated sodium bicarbonate, and brine, then driedover magnesium sulfate, filtered and concentrated to yield 330 mg ofcrude product. Purification by silica gel chromatography using an eluantof 1:1 to 2:1 ethyl acetate/hexanes gradient provided Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,tetrahydrofuran-3S-yl ester as a white solid. m/z=521 (M+H) calc.521.2311 obs. 521.2311.

EXAMPLE 16B

Preparation of Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,tetrahydrofuran-3S-yl ester

To a solution of 435 mg (1.0 mmol) of[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminein 3.0 mL of dimethylformamide was added 225 mg (0.98 mmol) ofN-succinimidyl-3S-tetrahydrofuranylcarbonate and the solution wasstirred overnight. The mixture was diluted with 50 mL of ethyl acetateand washed with 5% aqueous citric acid, saturated sodium bicarbonate,and brine, dried over magnesium sulfate, filtered and concentrated toyield 515 mg of crude product. Purificaton by silica gel chromatographyusing and eluant of 1:1 ethyl acetate:hexanes provided 315 mg ofCarbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,tetrahydrofuran-3S-yl ester, as a white solid. HRMS calc. 507.2165, obs.507.2155.

EXAMPLE 16C

Preparation of Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,tetrahydrothiophen-3S-yl ester,

To a solution of 215 mg (2.0 mmol) of 3S-hydroxythiophene, 415 μL ofanhydrous pyridine, and 2 mL of dry acetonitrile was added 512 mg (2.0mmol) of N,N′-Dimethylsuccinimidyl carbonate and this suspension wasstirred for 45 minutes. To this clear solution was added a solution of700 mg (1.7 mmol) of[2R-hydroxy-3-[[(4-methoxyyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminein 2.0 mL of acetonitrile and stirred for 12 hours. The contents wereconcentrated, and the residue was partitioned between ethyl acetate and5% aqueous potassium hydrogen sulfate. The organic layer was washed withsaturated sodium bicarbonate and then brine, dried over sodium sulfate,filtered and concentrated to yield 780 mg of crude material. Purificatonby silica gel chromatograpy using an eluant of 10:10:1 ethylacetate:hexane:methanol provided 520 mg of Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,tetrahydrothiophen-3S-yl-ester, as a crystalline white solid.m.p.=162-3° C., m/z=553 (M+H).

EXAMPLE 16D

Preparation of Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,1,1-dioxotetrahydrothiophen-3S-yl ester

To a solution of 270 mg (0.5 mmol) of Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,tetrahydrothiophen-3S-yl ester in 30 mL of dichloromethane was added 400mg (1.2 mmol) of m-chloroperbenzoic acid (50 wt %) and the mixture wasstirred for 12 hours. The contents were diluted with 10 mL of 10%aqueous sodium metabisulfite and stirred for 30 minutes. The organiclayer was washed with saturated sodium bicarbonate, dried over sodiumsulfate, filtered and concentrated to yield 290 mg of crude product.Purification by silica gel chromatography using an eluant of 10:10:1ethyl acetate:hexane:methanol provided 260 mg of Carbamic acid,[2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,1,1-dioxotetrahydrothiophen-3S-yl ester, as a white crystalline solid.m.p.=69° C., m/z=569 (M+H).

EXAMPLE 16E

Preparation of Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,tetrahydrothiophen-3S-yl ester

To a solution of 125 mg (1.2 mmol) of 3-S-hydroxythiophene, 250 μL ofanhydrous pyridine, and 1 mL of dry acetonitrile was added 307 mg (1.2mmol) of N,N′-dimethylsuccinimidyl carbonate and this suspension wasstirred for 45 minutes. To this clear solution was added a solution of445 mg (1.0 mmol)[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminein 1.0 mL of acetonitrile and stirred for 12 hours. The contents wereconcentrated, and the residue was partitioned between ethyl acetate and5% aqueous potassium hydrogen sulfate. The organic layer was washed withsaturated sodium bicarbonate and then brine, dried over sodium sulfate,filtered and concentrated to yield 460 mg of crude material. Purificatonby silica gel chromatograpy using an eluant of 10:10:1 ethylacetate:hexane:methanol provided 235 mg of Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,tetrahydrothiophen-3S-yl ester, as a crystalline white solid.m.p.=184-85° C. , m/z=529 (M+Li).

EXAMPLE 16F

Preparation of Carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,1,1-dioxotetrahydrothiophen-3S-yl ester

To a solution of 125 mg (0.24 mmol) of carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,tetrahydrothiophen-3S-yl ester in 30 mL of dichloromethane was added 240mg (0.7 mmol) of m-chloroperbenzoic acid (50 wt %) and the mixture wasstirred for 12 hours. The contents were diluted with 5 mL of 10% aqueoussodium metabisulfite and stirred for 30 minutes. The organic layer waswashed with saturated sodium bicarbonate, dried over sodium sulfate,filtered and concentrated to yield 110 mg of crude product. Purificationby silica gel chromatography using an eluant of 1:1 to 2:1 ethylacetate:hexane:methanol provided 100 mg of carbamic acid,[2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,1,1-dioxotetrahydrothiophen-3S-yl-ester, as a white crystalline solid,m.p.=190° C., m/z=561 (M+Li).

EXAMPLE 17A

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-thiazolylmethyl ester

Part A

Preparation of Methyl 2-aminothiazole-5-carboxylate

Methyl chloroacetate 190 g (1.75 mol) and methyl formate 111 g (1.80mol), were added dropwise to a suspension of 100 g (1.8 moL) of sodiummethoxide in 450 mL of dry toluene at 5° C. over 2 hours. After anadditional 2.5 hours at 0° C. The contents were diluted with 600 mL ofwater and the layers separated. The aqueous phase was acidified with 113mL of concentrated hydrochloric acid. The aqueous solution was placed ina 2 liter flask and 175 grams of thiourea was added and to solution washeated to reflux for 1.45 hours. To the cooled solution was added 25 gof DARCO activated charcoal and filtered through filter paper. The crudedark yellow solution was neutralized with 2.5 N sodium hydroxide uponwhich time an amber solid precipitated which was filtered and air driedto yield 147 g of desired methyl 2-aminothiazole-5-carboxylate.m/e=159(M+H).

Part B

Preparation of Methyl 5-thiazolecarboxylate

To a solution of 35 mL (30.5 g, 260 mmol) of isoamyl nitrite in. 120 mLof dioxane at 80° C. under nitrogen, was slowly added a slurry of 20.0 g(126 mmol) of methyl 2-amino-5-thiazolecarboxylate over a 45 minuteperiod. After refluxing for a further 1 hour, the solution was cooled,concentrated, dissolved in ethyl acetate, washed with saturated sodiumbicarbonate, brine, dried over magnesium sulfate, filtered andconcentrated to afford 28 g of the crude product. This waschromatographed on 400 g of silica gel using 20% ethyl acetate/hexane toafford 9.07 g of purified material, which was crystallized frommethylene chloride/hexane to yield 7.64 g of pure methyl5-thiazolylcarboxylate, m/e=144(M+H).

Part C

Preparation of 5-thiazolemethanol

To a solution of 11.73 g (82 mmol) of methyl 5-thiazolylcarboxylate in105 mL of anhydrous tetrahydrofuran at 0° C. under nitrogen, was added90 mL (90 mmol) of a 1.0M lithium aluminum hydride solution in diethylether over a 35 minute period. After stiiring at room temperature for 30minutes, the solution was cooled to 0° C., and carefully quenched by theaddition of 3 mL of water, 3 mL of 20% sodium hydroxide solution, and 6mL of water, then 100 mL of tetrahydrofuran was added. After stirringfor 1 hour, the mixture was filtered, the solid was washed withtetrahydrofuran, and the filtrate concentrated to afford 7.56 g of5-thiazolylmethanol.

Part D

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](methylpropyl)amino]-1S-(phenylmethyl)propyl]-,5-(thiazolyl)methyl ester

To a solution of 115 mg (1.00 mmol) of 5-(hydroxymethyl)thiazole in 3 mLof anhydrous acetonitrile, was added 0.25 mL (0.25 g, 3.09 mmol) ofpyridine and then 256 mg (1.03 mmol) of N,N′-disuccinimidyl carbonate atroom temperature under nitrogen. After 45 minutes, 406 mg (1.00 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-methoxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After stirring at room temperature for 15 hours, ethylacetate was added, washed with water, saturated sodium bicarbonate andbrine, dried over magnesium sulfate, filtered and concentrated to afford500 mg of crude product. This was chromatographed on silica gel using80% ethyl acetate/hexane as eluent to afford 307 mg of a white solid,which was identified as the desired carbamic acid,[2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,5-thiazolylmethyl ester, m/e=548(M+H).

EXAMPLE 17B

Preparation of Carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,5-thiazolylmethyl ester

To a solution of 115 mg (1.00 mmol) of 5-(hydroxymethyl)thiazole in 3 mLof anhydrous acetonitrile, was added 0.25 mL (0.25 g, 3.09 mmol) ofpyridine and then 256 mg (1.03 mmol) of N,N′-disuccinimidyl carbonate atroom temperature under nitrogen. After 45 minutes, 392 mg (1.00 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-hydroxyphenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After stirring at room temperature for 15 hours, ethylacetate was added, washed with water, saturated sodium bicarbonate andbrine, dried over magnesium sulfate, filtered and concentrated to afford450 mg of crude product. This was chromatographed on silica gel using80% ethyl acetate/hexane as eluent to afford 270 mg of a white solid,which was identified as the desired carbamic acid,[2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,5-thiazolylmethyl ester, m/e=534 (M+H).

EXAMPLE 18A

Preparation of2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine

Part A

Preparation of Carbamic acid,2R-hydroxy-3-[[(4-nitrophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester

To a solution of 4.0 g (10.8 mmol) ofN-(3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl]-N-isobutylamine in 50mL of anhydrous methylene chloride, was added 4.5 mL (3.27 g, 32.4 mmol)of triethylamine. The solution was cooled to 0° C. and 2.63 g (11.9mmol) of 4-nitrobenzene sulfonyl chloride was added, stirred for 30minutes at 0° C., then for 1 hour at room temperature. Ethyl acetate wasadded, washed with 5% citric acid, saturated sodium bicarbonate, brine,dried and concentrated to yield 5.9 g of crude material. This wasrecrystallized from ethyl acetate/hexane to afford 4.7 g of purecarbamic acid,[2R-hydroxy-3-[[(4-nitrophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester, m/e=556(M+H).

Part B

Preparation of2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine

A solution of 3.0 g (5.4 mmol) of carbamic acid,2R-hydroxy-3-[[(4-nitrophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester in 20 mL of ethyl acetate was hydrogenated over 1.5 gof 10% palladium-on-carbon catalyst under 35 psig of hydrogen for 3.5hours. The catalyst was removed by filtration and the solutionconcentrated to afford 2.05 g of the desired2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine,m/e=392 (M+H).

EXAMPLE 18B

Preparation of Carbamic acid,2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methyylropyl)amino]-1S-(phenylmethyl)propyl-,3-furanylmethyl ester

To a solution of 104 mg (1.06 mmol) of 3-(hydroxymethyl)furan in 2 mL ofanhydrous acetonitrile, was added 0.26 mL (0.25 g, 3.18 mmol) ofpyridine and then 277 mg (1.06 mmol) of N,N′-disuccinimidyl carbonate atroom temperature under nitrogen. After 45 minutes, 415 mg (1.06 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-aminophenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After stirring at-room temperature for 72 hours, ethylacetate was added, washed with 5% citric acid, saturated sodiumbicarbonate and brine, dried over magnesium sulfate, filtered andconcentrated to afford 550 mg of crude product. This was chromatographedon silica gel using 50% ethyl acetate/hexane as eluent to afford 230 mgof a white foam, which was identified as the desired carbamic acid,2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-furanylmethyl ester, m/e=522 (M+Li).

EXAMPLE 18C

Preparation of Carbamic acid,2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,5-thiazolylmethyl ester

To a solution of 118 mg (1.03 mmol) of 5-(hydroxymethyl)thiazole in 3 mLof anhydrous acetonitrile, was added 0.25 mL (0.24 g, 3.09 mmol) ofpyridine and then 264 mg (1.03 mmol) of N,N′-disuccinimidyl carbonate atroom temperature under nitrogen. After 45 minutes, 403 mg (1.03 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-aminophenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After stirring at room temperature for 15 hours, ethylacetate was added, washed with 5% citric acid, saturated sodiumbicarbonate and brine, dried over magnesium sulfate, filtered andconcentrated to afford 350 mg of crude product. This was chromatographedon silica gel using 80% ethyl acetate/hexane as eluent to afford 290 mgof a white solid, which was identified as the desired carbamic acid,2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,5-thiazolylmethyl ester, m/e=539 (M+Li).

EXAMPLE 18D

Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl

To a solution of 391 mg (1 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-aminophenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminein 3 mL of anhydrous methylene chloride, was added 0.42 mL (3 mmol) oftriethylamine, then at room temperature, 0.12 mL (0.9 mmol) ofortho-toluoyl chloride was added. After 15 hours at room temp ethylacetate was added, washed with 5% citric acid, saturated sodiumbicarbonate, brine, dried, filtered and concentrated to afford 420 mg ofcrude material. This was chromatographed on 40 g of silica gel using 50%ethyl acetate/hexane to afford 368 mg of pure benzamide,N-[2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-2-methyl,m/e=516(M+Li).

EXAMPLE 18E

Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-hydroxy-2-methyl

Part A

Preparation of 3-Hydroxy-2-methylbenzoic Acid

A one-necked 100 mL round-bottomed flask (magnetic stirring) was chargedwith 1.0 gram (6.6 mM) 3-amino-2-methylbenzoic acid. A warm mixture of2.3 mL conc. sulfuric acid in 4.3 mL water was added to the flask, theresulting slurry was cooled below 15° C. in an ice bath, and 6.6 gramsof ice was added. The reaction mixture was treated via subsurfaceaddition with a solution of 0.6 gram (8.6 mM) sodium nitrite in 6.6 mLice water with the reaction temperature maintained at 0-5° C. during theaddition. After stirring at 0-5° C. for 30 min., a few crystals of ureawere added to decompose the excess nitrite. The reaction mixture wasthen poured into a room temperature solution of 23.8 grams (102.3 mM)copper (II) nitrate hemipentahydrate in 200 mL water. With vigorousstirring, the reaction mixture was treated with 0.9 gram (6.0 mM) copper(I) oxide. The reaction mixture foamed and changed from turquoise blueto dark green in color. Reaction was left stirring for 30 min. Thereaction mixture was extracted with diethyl ether (3×), and the organicextracts were combined. The organic extracts were concentrated toapproximately one-fourth the original volume, then extracted with 25 mL1N sodium hydroxide solution. The layers were separated, and thedark-red aqueous layer was acidified to pH=2 using 1N hydrochloric acidsolution. The acidified aqueous layer was then extracted with diethylether (3×), and the ether extracts were combined, dried (MgSO₄), andconcentrated to yield a reddish-colored oil. Purification by flashchromatography on silica gel using a gradient of 0-7% methanol/methylenechloride afforded 0.39 grams (36%) of a yellow solid.

Part B

Preparation of Benzamide,N-[2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-hydroxy-2-methyl

To a solution of 175 mg (1.15 mmol) of 3-hydroxy-2-1methylbenzoic acidand 203 mg (1.5 mmol) of N-hydroxybenzotriazole in 6 mL of anhydrousN,N-dimethylformamide at 0° C., was added 220 mg (1.15 mmol) of EDC.After 20 minutes of activation at 0° C. and 1 hour at room temperature,392 mg (1.0 mmol) of2R-hydroxy-3-[(2-methylpropyl)(4-aminophenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After 15 hours at room temperature, ethyl acetate was added,washed with 5% citric acid, saturated sodium bicarbonate, brine, dried,filtered and concentrated to afford 590 mg of crude material. This waschromatographed on silica gel using 50-80% ethyl acetate/methylenechloride as eluent to afford 255 mg of pure benzamide,N-[2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino)-1S-(phenylmethyl)propyl]-3-hydroxy-2-methyl,m/e=526(M+H).

EXAMPLE 18F

Preparation of Carbamic acid,2R-hydroxy-3-[[(2-aminobenzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester

Carbamic acid,2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester 0.30 g (0.571 mmol) was added to a well mixed powderof anhydrous copper sulfate (1.20 g) and potassium thiocyanate (1.50 g)followed by dry methanol (6 mL) and the resulting black-brown suspensionwas heated at reflux for 2 hrs. The reaction mixture was filtered andthe filtrate was diluted with water (5 mL) and heated at reflux. Ethanolwas added to the reaction mixture, cooled and filtered. The filtrateupon concentration afforded a residue which was chromatographed (ethylacetate:hexane 80:20) to afford 0.26 g (78%) of the desired compound asa solid.

EXAMPLE 18G

Preparation of Carbamic acid,2R-hydroxy-3-[[(benzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester

Carbamic acid,2R-hydroxy-3-[[(2-aminobenzothiazol-6-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester (0.25 g, 0.429 mmol) was added to a solution ofisoamylnitrite (0.116 mL, 0.858 mmol) in dioxane (5 mL) and the mixturewas heated at 85° C. After the cessation of evolution of nitrogen, thereaction mixture was concentrated and the residue was purified bychromatography (hexane:ethyl acetate 5:3) to afford 0.130 a (53%) of thedesired product as a solid.

EXAMPLE 19A

Preparation of2R-hydroxy-3-[[(3-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine

Part A

Preparation of Carbamic acid,[2R-hydroxy-3-[(3-nitrophenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester

To a solution of 1.1 g (3.0 mmol) ofN-[3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl]-N-isobutylamine in 15mL of anhydrous methylene chloride, was added 1.3 mL (0.94 g, 9.3 mmol)of triethylamine. The solution was cooled to 0° C. and 0.67 g (3.0 mmol)of 3-nitrobenzene sulfonyl chloride was added, stirred for 30 minutes at0° C., then for 1 hour at room temperature. Ethyl acetate was added,washed with 5% citric acid, saturated sodium bicarbonate, brine, driedand concentrated to yield 1.74 g of crude material. This wasrecrystallized from ethyl acetate/hexane to afford 1.40 g of purecarbamic acid,(2R-hydroxy-3-[(3-nitrophenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester, m/e=562(M+Li).

Part B

Preparation of[2R-hydroxy-3-[[(3-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine

A solution of 1.33 g (2.5 mmol) of carbamic acid,(2R-hydroxy-3-[(3-nitrophenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester in 40 mL of 1:1 methanol/tetrahydrofuran washydrogenated over 0.70 g of 10% palladium-on-carbon catalyst under 40psig of hydrogen for 1.5 hours. The catalyst was removed by filtrationand the solution concentrated to afford 0.87 g of the desired[2R-hydroxy-3-[[(3-aminophenyl)sulfonyl](2-methylpropyl)amino)-1S-(phenylmethyl)propylamine.

EXAMPLE 19B

Preparation of Carbamic acid,2R-hydroxy-3-[[(3-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,5-thiazolylmethyl ester

To a solution of 133 mg (1.15 mmol) of 5-(hydroxymethyl)thiazole in 3 mLof anhydrous acetonitrile, was added 0.30 mL (0.29 g, 3.7 mmol) ofpyridine and then 296 mg (1.15 mmol) of N,N′-disuccinimidyl carbonate atroom temperature under nitrogen. After 60 minutes, 460 mg (1.18 mmol) of2R-hydroxy-3-[(2-methylpropyl)(3-aminophenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After stirring at room temperature for 15 hours, ethylacetate was added, washed with 5% citric acid, saturated sodiumBicarbonate and brine, dried over magnesium sulfate, filtered andconcentrated to afford 480 mg of crude product. This was chromatographedon silica gel using 50-80% ethyl acetate/hexane as eluent to afford 422mg of a white solid, which was identified as the desired carbamic acid,2R-hydroxy-3-[(3-aminophenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,5-thiazolylmethyl ester, m/e=539 (M+Li).

EXAMPLE 19C

Preparation of Benzamide,N-[2R-hydroxy-3-[[(3-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-hydroxy-2-methyl

To a solution of 134 mg (0.88 mmol) of 3-hydroxy-2-methylbenzoic acidand 155 mg (1.15 mmol) of N-hydroxybenzotriazole in 5 mL of anhydrousN,N-dimethylformamide at 0° C., was added 167 mg (0.88 mmol) of EDC.After 20 minutes of activation at 0° C. and 1 hour at room temperature,300 mg (1.0 mmol) of2R-hydroxy-3-[(2-methylpropyl)(3-aminophenyl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After 15 hours at room temperature, ethyl acetate was added,washed with 5% citric acid, saturated sodium bicarbonate, brine, dried,filtered and concentrated to afford 330 mg of crude material. This waschromatographed on silica gel using 30-70% ethyl acetate/methylenechloride as eluent to afford 230 mg of pure benzamide,N-[2R-hydroxy-3-[[(3-aminophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-hydroxy-2-methyl.

EXAMPLE 19D

Preparation of Carbamic acid, 2R-hydroxy-3-[[(2-aminobenzothiazol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester; and Carbamic acid,2R-hydroxy-3-[[(2-aminobenzothiazol-7-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester

The carbamic acid,2R-hydroxy-3-[(3-aminophenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester 0.36 g (0.685 mmol) was added to a well mixed powderof anhydrous copper sulfate (1.44 g) and potassium thiocyanate (1.80 g)followed by dry methanol (10 mL) and the rsulting black-brown suspensionwas heated at reflux for 2 hrs. The reaction mixture was filtered andthe filtrate was diluted with water (5 mL) and heated at reflux. Ethanolwas added to the reaction mixture, cooled and filtered. The filtrateupon concentration afforded a rseidue which was chromatographed (ethylacetate:hexane 1:1) to afford 0.18 g (45%) of the 7-isomer as a solid.Further elution of the column with (ethyl acetate:hexane 3:2) afforded0.80 g (20%) afforded the 5-isomer-as a solid.

EXAMPLE 20A

Preparation of2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine

Part A

Preparation of 5-(2,3-dihydrobenzofuranyl)sulfonyl chloride

To a solution of 3.35 g of anhydrous N,N-dimethylformamide at 0° C.under nitrogen was added 6.18 g of sulfuryl chloride, whereupon a solidformed. After stirring for 15 minutes, 4.69 g of 2,3-dihydrobenzofuranwas added, and the mixture heated at 100° C. for 2 hours. The reactionwas cooled, poured into ice water, extracted with methylene chloride,dried over magnesium sulfate, filtered and concentrated the crudematerial. This was recrystallized from ethyl acetate to afford 2.45 g of5-(2,3-dihydrobenzofuranyl)sulfonyl chloride.

Part B

Preparation of Carbamic acid,2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester

To a solution of 1.11 g (3.0 mmol) ofN-[3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl]-N-isobutylamine in 20mL of anhydrous methylene chloride, was added 1.3 mL (0.94 g, 9.3 mmol)of triethylamine. The solution was cooled to 0° C. and 0.66 g of5-(2,3-dihydrobenzofuranyl)sulfonyl chloride was added, stirred for 15minutes at 0° C., then for 2 hour at room temperature. Ethyl acetate wasadded, washed with 5% citric acid, saturated sodium bicarbonate, brine,dried and concentrated to yield 1.62 g of crude material. This wasrecrystallized from diethyl ether to afford 1.17 g of pure carbamicacid,[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester.

Part C

Preparation of[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine

A solution of 2.86 g of carbamic acid,[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester in 30 mL of tetrahydrofuran was hydrogenated 0.99 gof 10% palladium-on-carbon under 50 psig of hydrogen for 16 hours. Thecatalyst was removed by filtration and the filtrate concentrated toafford 1.99 g of the desired[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine.

EXAMPLE 20B

Preparation of Carbamic acid,[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-pyridylmethyl ester

To a solution of 110 mg of 3-pyridylcarbinol in 3 mL of anhydrousacetonitrile, was added 0.24 g of anhydrous pyridine and then 260 mg ofN,N′disuccinimidyl carbonate at room temperature under nitrogen. After45 minutes, 420 mg of2R-hydroxy-3-[(2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After stirring at room temperature for 20 hours, ethylacetate was added, washed with 5% citric acid, saturated sodiumbicarbonate and brine, dried over magnesium sulfate, filtered andconcentrated to afford 320 mg of crude product. This was chromatographedon silica gel using 50% ethyl acetate/hexane as eluent to afford 260 mgof a white solid, which was identified as the desired carbamic acid,[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-pyridylmethyl ester.

EXAMPLE 20C

Preparation of Carbamic acid,[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,5-thiazolylmethyl ester

To a solution of 66 mg of 5-(hydroxymethyl)thiazole in 3 mL of anhydrousacetonitrile, was added 0.14 g of anhydrous pyridine and then 150 mg ofN,N′-disuccinimidyl carbonate at room temperature under nitrogen. After45 minutes, 240 mg of2R-hydroxy-3-[(2-methylpropyl)(2,3-dihydrobenzofuran-5-yl)sulfonyl]amino-1S-(phenylmethyl)propylaminewas added. After stirring at room temperature for 20 hours, ethylacetate was added, washed with 5% citric acid, saturated sodiumbicarbonate and brine, dried over magnesium sulfate, filtered andconcentrated to afford 220 mg of crude product. This was chromatographedon silica gel using 50% ethyl acetate/hexane as eluent to afford 120 mgof a white solid, which was identified as the desired carbamic acid,[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,5-thiazolylmethyl ester.

EXAMPLE 20D

Preparation of Benzamide,N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-(phenylmethyl)propyl]-3-amino-2-methyl-

To a solution of 175 mg of 3-amino-2-methylbenzoic acid in 2 ml ofanhydrous N,N-dimethylformamide at 0° C., was added 200 mg ofN-hydroxybenzotriazole and then 210 mg of EDC. After 20 minutes ofactivation, 405 mg of2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminewas added. After stirring at room temperature for 16 hours, ethylacetate was added, wshed with 5% citric acid, sodium bicarbonate, brine,dried over magnesium sulfate, filtered and concentrated to afford 225 mgof crude product. This was chromatographed on silica gel using 50% ethylacetate/hexane to afford 140 mg of the desired benzamide,N-[2R-hydroxy-3-[[(2,3-dihydrobenzofuran-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-amino-2-methyl,m/e=552 (M+H).

EXAMPLE 21A

Preparation of2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine

Part A

Preparation of (1,3-Benzodioxol-5-yl)sulfonyl chloride

To a solution of 4.25 g of anhydrous N,N-dimethylformamide at 0° C.under nitrogen was added 7.84 g of sulfuryl chloride, whereupon a solidformed. After stirring for 15 minutes, 6.45 g of 1,3-benzodioxole wasadded, and the mixture heated at 100° C. for 2 hours. The reaction wascooled, poured into ice water, extracted with methylene chloride, driedover magnesium sulfate, filtered and concentrated to give 7.32 g ofcrude material as a black oil. This was chromatographed on silica gelusing 20% methylene chloride/hexane to afford 1.9 g of(1,3-benzodioxol-5-yl)sulfonyl chloride.

Part B

Preparation of Carbamic acid,2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester

To a solution of 3.19 g(8.6 mmol) of N-[3S-benzyloxycarbonylamino-2R-hydroxy-4-phenyl]-N-isobutylamine in 40 mL of anhydrousmethylene chloride, was added 0.87 g of triethylamine. The solution wascooled to 0° C. and 1.90 g of (1,3-benzodioxol-5-yl)sulfonyl chloridewas added, stirred for 15 minutes at 0° C., then for 17 hours at roomtemperature. Ethyl acetate was added, washed with 5% citric acid,saturated sodium bicarbonate, brine, dried and concentrated to yieldcrude material. This was recrystallized from diethyl ether/hexane toafford 4.77 g of pure carbamic acid,2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester.

Part C

Preparation of2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine

A solution of 4.11 g of carbamic acid,2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,phenylmethyl ester in 45 mL of tetrahydrofuran and 25 mL of methanol washydrogenated over 1.1 g of 10% palladium-on-carbon under 50 psig ofhydrogen for 16 hours. The catalyst was removed by filtration and thefiltrate concentrated to afford 1.82 g of the desired2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine.

EXAMPLE 21B

Preparation of Carbamic acid,2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-pyridylmethyl ester

To a solution of 110 mg of 3-pyridylcarbinol in 3 mL of anhydrousacetonitrile, was added 0.24 g of anhydrous pyridine and then 260 mg ofN,N′disuccinimidyl carbonate at room temperature under nitrogen. After45 minutes, 410 mg of2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminewas added. After stirring at room temperature for 20 hours, ethylacetate was added, washed with 5% citric acid, saturated sodiumbicarbonate and brine, dried over magnesium sulfate, filtered andconcentrated to afford 330 mg of crude product. This was chromatographedon silica gel using 50% ethyl acetate/hexane as eluent to afford 160 mgof a white solid, which was identified as the desired carbamic acid,[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,3-pyridylmethyl ester, m/e=562(M+Li).

EXAMPLE 21C

Preparation of Carbamic acid,2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,5-thiazolylmethyl ester

To a solution of 85 mg (0.8 mmol) of 5-(hydroxymethyl)thiazole in 2.2 mLof anhydrous acetonitrile, was added 0.18 mL (2.2 mmol) of anhydrouspyridine and then 189 mg (0.74 mmol) of N,N′-disuccinimidyl carbonate atroom temperature under nitrogen. After 45 minutes, 310 mg of2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminewas added. After stirring at room temperature for 20 hours, ethylacetate was added, washed with 5% citric acid, saturated sodiumbicarbonate and brine, dried over magnesium sulfate, filtered andconcentrated to afford 300 mg of crude product. This was chromatographedon silica gel using 50% ethyl acetate/hexane as eluent to afford 150 mgof a white solid, which was identified as the desired carbamic acid,2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl-,5-thiazolylmethyl ester, m/e=568(M+Li).

EXAMPLE 21D

Preparation of Benzamide,N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-amino-2-methyl

To a solution of 175 mg of 3-amino-2-methylbenzoic acid in 2 mL ofanhydrous N,N-dimethylformamide at 0° C., was added 200 mg ofN-hydroxybenzotriazole and then 210 mg of EDC. After 20 minutes ofactivation, 410 mg of2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminewas added. After stirring at room temperature for 16 hours, ethylacetate was added, washed with 5% citric acid, sodium bicarbonate,brine, dried over magnesium sulfate, filtered and concentrated to afford500 mg of crude product. This was chromatographed on silica gel using50% ethyl acetate/hexane to afford 310 mg of the desired benzamide,N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-amino-2-methyl,m/e=560(M+Li).

EXAMPLE 21E

Preparation of Benzamide,N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-4-hydroxy-2-methyl

Part A

Preparation of 2-Trimethylsilyloxy-1,3-cyclohexadiene

A 100 mL round bottom flask equipped with magnetic stir bar, additionfunnel, and N₂ inlet was charged with 40 mL dry THF and 8.3 mLdiisopropyl amine. The solution was cooled to −78° C. and charged with23.8 mL of 2.5M nBuLi in Hexane. After 10 minutes a solution of 5.2 gcyclohexenone in 10 mL THF was added dropwise. The reaction was stirred10 minutes at −78° C. and quenched with 7.5 mL trimethylsilyl chloride.The reaction was stirred 15 minutes and then partitioned between diethylether and cold saturated aqueous sodium bicarbonate. The combinedorganic layers were dried over sodium sulfate and concentrated in vacuoto a yellow oil. Short path distillation (BP 27-29° C./0.5 mm) afforded6.0 g (66%) of 2-Trimethylsilyloxy-1,3-Cyclohexadiene.

Part B

Preparation of Methyl (2-methyl-4-trimethylsilyoxy)benzoate

A 50 mL round bottom flask equipped with magnetic stir bar and condenserwas charged with 6.0 g of 2-trimethylsilyloxy-1,3-cyclohexadiene, 3.5 gmethyl tetrolate in 3 mL dry toluene. The reaction was heated to 150° C.for 50 hours at which point ¹H-NMR indicated no starting diene. Theraction was concentrated in vacuo to provide 5.7 g (67%) methyl2-methyl-4-trimethylsilyloxybenzoate.

Part C

Preparation of 4-Hydroxy-2-methylbenzoic acid

A 100 mL round bottom flask equipped with magnetic stir bar was chargedwith 5.7 g methyl 2-methyl-4-trimethylsilyloxybenzoate and 2.0 g LiOH in40 mL methanol and 10 mL water. After 2 hours at reflux the reaction waspoured into 10 mL concentrated HCl and then 100 g ice. Extraction withethyl acetate followed by concentration in vacuo gave a crude solid(70:30) product:starting material. Flash Chromatography using 50-50ethyl acetate/hexanes as an eluent gave 1.15 g 2-methyl-4-hydroxybenzoicacid, m/e=193(M+H).

Part D

Preparation of Benzamide,N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-4-hydroxy-2-methyl

To a solution of 175 mg of 4-hydroxy-2-methylbenzoic acid in 2 mL ofanhydrous N,N-dimethylformamide at 0° C., was added 200 mg ofN-hydroxybenzotriazole and then 220 mg of EDC. After 20 minutes ofactivation, 450 mg of2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminewas added. After stirring at room temperature for 16 hours, ethylacetate was added, wshed with 5% citric acid, sodium bicarbonate, brine,dried over magnesium sulfate, filtered and concentrated to afford crudeproduct. This was chromatographed on silica gel using 50% ethylacetate/hexane to afford 102 mg of the desired benzamide,N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-4-hydroxy-2-methyl.

EXAMPLE 21F

Preparation of Benzamide,N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-hydroxy-2-methyl

To a solution of 187 mg (1.23 mmol) of 3-hydroxy-2-methylbenzoic acidand 217 mg (1.61 mmol) of N-hydroxybenzotriazole in 6 mL of anhydrousN,N-dimethylformamide at 0° C., was added 236 mg (1.23 mmol) of EDC.After 20 minutes of activation at 0° C. and 1 hour at room temperature,450 mg (1.07 mmol) of2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylaminewas added. After 15 hours at room temperature, ethyl acetate was added,washed with 5% citric acid, saturated sodium bicarbonate, brine, dried,filtered and concentrated to afford 650 mg of crude material. This waschromatographed on silica gel using 0-25% ethyl acetate/methylenechloride as eluent to afford 390 mg of pure benzamide,N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-hydroxy-2-methyl,m/e=561(M+Li).

EXAMPLE 22

Following the procedures of Examples 1-21, the compounds shown in Tables3, 5A and 5B were prepared and in Tables 4 through 17 can be prepared.

TABLE 3

Entry No. R R¹ R³ R⁴ 1 Cbz t-Butyl i-Amyl Methyl 2 N,N-Dimethyl- t-Butyli-Amyl Methyl glycine 3 Cbz i-Propyl i-Amyl Phenyl 4 Cbz sec-Butyli-Amyl Phenyl 5 Cbz CH₂C(O)NH₂ n-Propyl Phenyl 6 N-Methylglycine t-Butyli-Amyl Phenyl 7 Cbz t-Butyl i-Butyl Phenyl 8 N,N-Dimethyl- t-Butyli-Amyl Phenyl glycine 9 N-Methylglycine t-Butyl i-Amyl Phenyl 10 N,N-Dimethyl- t-Butyl i-Butyl (4-OCH₃)Phenyl glycine 11  N-Methylglycinet-Butyl i-Butyl (4-OCH₃)Phenyl

TABLE 4

Entry No. R R³ R⁴  1 Cbz^(a) CH₃ n-Butyl  2 Cbz i-Butyl CH₃  3 Cbzi-Butyl n-Butyl  4 Q^(b) i-Butyl n-Butyl  5 Cbz i-Propyl n-Butyl  6 Qi-Propyl n-Butyl  7 Cbz C₆H₅ n-Butyl  8 Cbz

n-Butyl  9 Cbz

n-Butyl  10 Q

n-Butyl  11 Cbz

n-Butyl  12 Cbz i-Butyl n-Propyl  13 Cbz i-Butyl —CH₂CH(CH₃)₂  14 Cbz

n-Butyl  15 Cbz

i-Propyl  16 Cbz

—CH₂CH₂CH(CH₃)₂  17 Cbz i-Butyl —CH₂CH₃  18 Cbz i-Butyl —CH(CH₃)₂  19Cbz i-Butyl

 20 Q -Butyl

 21 Cbz

—(CH₂)₂CH(CH₃)₂  22 Cbz (CH₂)₂CH(CH₃)₂ —CH(CH₃)₂  23 Q i-Butyl —CH(CH₃)₂ 24 Cbz i-Butyl —C(CH₃)₃  25 Q i-Butyl —C(CH₃)₃  26 Cbz

—C(CH₃)₃  27 Q

—C(CH₃)₃  28 Cbz —(CH₂)₂CH(CH₃)₂ —C(CH₃)₃  29 Q —(CH₂)₂CH(CH₃)₂ —C(CH₃)₃ 30 Cbz —CH₂C₆H₅ —C(CH₃)₃  31 Q —CH₂C₆H₅ —C(CH₃)₃  32 Cbz —(CH₂)₂C₆H₅—C(CH₃)₃  33 Cbz —(CH₂)₂C₆H₅ —C(CH₃)₃  34 Cbz n-Butyl —C(CH₃)₃  35 Cbzn-Pentyl —C(CH₃)₃  36 Cbz n-Hexyl —C(CH₃)₃  37 Cbz

—C(CH₃)₃  38 Cbz —CH₂C(CH₃)₃ —C(CH₃)₃  39 Q —CH₂C(CH₃)₃ —C(CH₃)₃  40 Cbz

—C(CH₃)₃  41 Cbz —CH₂C₆H₅OCH₃(para) —C(CH₃)₃  42 Cbz

—C(CH₃)₃  43 Cbz

—C(CH₃)₃  44 Cbz —(CH₂)₂C(CH₃)₃ —C(CH₃)₃  45 Q —(CH₂)₂C(CH₃)₃ —C(CH₃)₃ 46 Cbz —(CH₂)₄OH —C(CH₃)₃  47 Q —(CH₂)₄OH —C(CH₃)₃  48 Q

—C(CH₃)₃  49 Q

—C(CH₃)₃  50 Cbz —CH₂CH(CH₃)₂ —C₆H₅  51

—CH₂CH(CH₃)₂ —C₆H₅  52

—CH₂CH(CH₃)₂ —C₆H₅  53

—CH₂CH(CH₃)₂ —C₆H₅  54

—CH₂CH(CH₃)₂ —C₆H₅  55

—CH₂CH(CH₃)₂ —C₆H₅  56

—CH₂CH(CH₃)₂ —C₆H₅  57

—CH₂CH(CH₃)₂ —C₆H₅  58

—CH₂CH(CH₃)₂ —C₆H₅  59

—CH₂CH(CH₃)₂ —C₆H₅  60

—CH₂CH(CH₃)₂ —C₆H₅  61

—CH₂CH(CH₃)₂ —C₆H₅  62

—CH₂CH(CH₃)₂ —C₆H₅  63

—CH₂CH(CH₃)₂ —C₆H₅  64

—CH₂CH(CH₃)₂ —C₆H₅  65

—CH₂CH(CH₃)₂ —C₆H₅  66

—CH₂CH(CH₃)₂ —C₆H₅  67

—CH₂CH(CH₃)₂ —C₆H₅  68

—CH₂CH(CH₃)₂ —C₆H₅  69

—CH₂CH(CH₃)₂ —C₆H₅  70 Q —CH₂Ph —Ph  71 Q

—Ph  72 Q

—Ph  73 Q

—Ph  74 Q

—Ph  75 Q

—Ph  76 Q —CH₂CH═CH₂ —Ph  77 Q

—Ph  78 Q

—Ph  79 Q —CH₂CH₂Ph —Ph  80 Q —CH₂CH₂CH₂CH₂OH —Ph  81 Q —CH₂CH₂N(CH₃)₂—Ph  82 Q

—Ph  83 Q —CH₃ —Ph  84 Q —CH₂CH₂CH₂SCH₃ —Ph  85 Q —CH₂CH₂CH₂S(O)₂CH₃ —Ph 86 Q —CH₂CH₂CH₂CH(CH₃)₂

 87 Q —CH₂CH₂CH(CH₃)₂

 88 Q —CH₂CH₂CH(CH₃)₂ —CH₂CH₂CH₃  89 Q —CH₂CH₂CH₂CH(CH₃)₂ —CH₃  90 Q—CH₂CH₂CH(CH₃)₂

 91 Q —CH₂CH₂CH(CH₃)₂

 92 Q —CH₂CH₂CH(CH₃)₂

 93 Q —CH₂CH₂CH(CH₃)₂

 94 Q —CH₂CH₂CH(CH₃)₂

 95 Q —CH₂CH₂CH(CH₃)₂

 96 Q —CH₂CH₂CH(CH₃)₂

 97 Q —CH₂CH₂CH(CH₃)₂

 98 Q —CH₂CH₂CH(CH₃)₂

 99 Q —CH₂CH₂CH(CH₃)₂

100 Q —CH₂CH₂CH(CH₃)₂

101 Q —CH₂CH₂CH(CH₃)₂

102 Q —CH₂CH₂CH(CH₃)₂

103 Q —CH₂CH(CH₃)₂

104 Q —CH₂CH(CH₃)₂

105 Q —CH₂CH(CH₃)₂

106 Q —CH₂CH₂CH₃

107 Q —CH₂CH₂CH₂CH₃

^(a)benzyloxycarbonyl ^(b)2-quinolinylcarbonyl

TABLE 5

Entry A R³ R⁴ 1 Cbz-Val i-amyl —C₆H₅ 2 Cbz-Leu i-amyl —C₆H₅ 3 Cbz-Ilei-amyl —C₆H₅ 4 Ac-D-homo-Phe i-Bu methyl 5 Qui-Orn(g-Cbz)

—C₆H₅ 6 Cbz-Asn —CH₂CH═CH₂ —C₆H₅ 7 Acetyl-t-BuGly i-amyl —C₆H₅ 8Acetyl-Phe i-amyl —C₆H₅ 9 Acetyl-Ile i-amyl —C₆H₅ 10 Acetyl-Leu i-amyl—C₆H₅ 11 Acetyl-His i-amyl —C₆H₅ 12 Acetyl-Thr i-amyl —C₆H₅ 13Acetyl-NHCH(C(CH₃)₂(SCH₃))C(O)— i-amyl —C₆H₅ 14 Cbz-Asn i-amyl —C₆H₅ 15Cbz-Ala i-amyl —C₆H₅ 16 (N,N-dimethylglycinyl)Val i-amyl —C₆H₅ 17(N-methylglycinyl)Val i-amyl —C₆H₅ 18 (N,N-dimethylglycinyl)Ile i-amyl—C₆H₅ 19 (N-methylglycinyl)Ile i-amyl —C₆H₅ 20 Cbz-Ala i-amyl —C₆H₅ 21Cbz-beta-cyanoAla i-amyl —C₆H₅ 22 Cbz-t-BuGly i-amyl —C₆H₅ 23 Q-t-BuGlyi-amyl —C₆H₅ 24 Q-SCH₃Cys i-amyl —C₆H₅ 25 Cbz-SCH₃Cys i-amyl —C₆H₅ 26Q-Asp i-amyl —C₆H₅ 27 Cbz-(NHCH(C(CH₃)₂(SCH₃))C(O)— i-amyl —C₆H₅ 28Cbz-EtGly i-amyl —C₆H₅ 29 Cbz-PrGly i-amyl —C₆H₅ 30 Cbz-Thr i-amyl —C₆H₅31 Q-Phe i-amyl —C₆H₅ 32 Cbz-Phe i-amyl —C₆H₅ 33

i-Butyl —C₆H₄

TABLE 5A

MASS MEASUREMENT CALC Entry R³ R⁴ R⁷ MOL FORM M + H FOUND 1

C₂₇H₃₈N₂O₅S 503.2661 503.2624 2

C₂₈H₄₀N₂O₅S 517.2736 517.2777 3

C₂₉H₄₂N₂O₅S 531.2893 531.2916 4

C₃₂H₄₀N₂O₅S 565.2736 565.2731 5

C₃₀H₃₅N₃O₅S 550.2376 550.2427 6

C₃₀H₃₈N₂O₅S 539 (M + H) 539 7

C₂₉H₃₆N₂O₅S ? ? 8 C₃₀H₃₈N₂O₅S 539.2580 (M + H) 539.2591 9

C₂₇H₃₃N₃O₅S 512.2219 512.2271 10

C₂₈H₃₅N₃O₅S 526.2376 526.2388 11

C₂₇H₃₃N₃O₅S 512.2219 512.2287 12

C₂₈H₃₃N₂O₅CIS 545.1877 545.1887 13

C₃₀H₃₈N₂O₅S 539.2580 539.2592 14

C₃₁H₄₀N₂O₅S 553.2736 553.2714 15

C₃₀H₃₈N₂O₅S 539.2580 539.2632 16

C₃₀H₃₈N₂O₅S 539 (M + H) 539 17

C₂₉H₃₆N₂O₇S₂ 589.2042 (M + H) 589.2086 18

C₂₉H₃₆N₂O₇S₂ 595.2124 (M + Li) 595.2103 19

C₂₉H₃₆N₂O₇S₂ 595.2124 (M + Li) 595.2191 20

C₃₀H₃₈N₂O₇S₂ 609.2281 (M + Li) 609.2313 21

C₃₀H₃₈N₂O₇S₂ 603.2199 (M + H) 603.2247 22

C₃₀H₃₈N₂O₇S₂ 603.2199 (M + H) 603.2266 23

24

C₂₇H₃₂N₂O₄S 481.2161 481.2213 25

C₂₈H₃₅N₂O₅S 511.2267 511.2319 26

C₂₉H₃₆N₂O₅S 525.2423 525.2469 27

C₂₉H₃₆N₂O₅S 525.2428 525.2464 28

C₂₉H₃₆N₂O₅S 525.2423 525.2432 29

C₂₉H₃₆N₂O₆S 541.2372 541.2332 30

C₂₉H₃₆N₂O₆S 541.2372 541.2355 31

C₂₉H₃₆N₂O₆S 541.2372 541.2329

TABLE 5B

Molecular Mass Entry A Formula Spectrum

C₂₉H₃₅N₃O₇S 576 (M + Li)

C₂₉H₃₇N₃O₅S 540 (M + H)

C₃₁H₄₁N₃O₅S 568 (M + H)

C₂₉H₃₅N₃O₇S 570 (M + H)

C₂₉H₃₇N₃O₅S 540 (M + H)

C₃₁H₄₁N₃O₅S 568 (M + H)

C₂₉H₃₅N₃O₇S 570 (M + H)

C₂₉H₃₇N₃O₅S 546 (M + Li)

C₃₁H₄₁N₃O₅S 574 (M + Li)

TABLE 6

Entry R¹ 1 CH₂SO₂CH₃ 2 (R)—CH(OH)CH₃ 3 CH(CH₃)₂ 4 (R,S)CH₂SOCH₃ 5CH₂SO₂NH₂ 6 CH₂SCH₃ 7 CH₂CH(CH₃)₂ 8 CH₂CH₂C(O)NH₂ 9 (S)—CH(OH)CH₃ 10—CH₂C≡C—H

TABLE 7

Entry R² A 1 n-Bu Cbz-Asn 2 cyclohexylmethyl Cbz-Asn 3 n-Bu Boc 4 n-BuCbz 5 C₆H₅CH₂ Boc 6 P—F—C₆H₅CH₂ Cbz 7 C₆H₅CH₂ benzoyl 8 cyclohexylmethylCbz 9 n-Bu Q-Asn 10 cyclohexylmethyl Q-Asn 11 C₆H₅CH₂ Cbz-Ile 12 C₆H₅CH₂Q-Ile 13 P—F—C₆H₅CH₂ Cbz-t-BuGly 14 C₆H₅CH₂ Q-t-BuGly 15 C₆H₅CH₂ Cbz-Val16 C₆H₅CH₂ Q-Val 17 2-naphthylmethyl Cbz-Asn 18 2-naphthylmethyl Q-Asn19 2-naphthylmethyl Cbz 20 n-Bu Cbz-Val 21 n-Bu Q-Val 22 n-Bu Q-Ile 23n-Bu Cbz-t-BuGly 24 n-Bu Q-t-BuGly 25 p-F(C₆H₄)CH₂ Q-Asn 26 p-F(C₆H₄)CH₂Cbz 27 p-F(C₆H₄)CH₂ Cbz-Asn 28 C₆H₅CH₂ Cbz-propargylglycine 29 C₆H₅CH₂Q-propargylglycine 30 C₆H₅CH₂ acetylpropargylglycine

TABLE 8

Entry R³ R⁴ 1 —CH₂CH(CH₃)₂ —C(CH₃)₂ 2 —CH₂CH₂CH(CH₃)₂

3 —CH₂CH₂CH(CH₃)₂

4 —CH₂CH₂CH(CH₃)₂

5 —CH₂CH₂CH(CH₃)₂

TABLE 9

Entry R R¹ 1

—CH₃ 2

—CH₃ 3

—CH(CH₃)₂ 4

—CH(CH₃)₂ 5

—C(CH₃)₃ 6

—CH₃ 7

—CH₃ 8

—CH₃ 9

—CH₃ 10

—CH₃ 11

—CH₃ 12

—CH₃ 13

—CH₃ 14

—CH₃ 15

16

TABLE 10

Entry R¹ R^(1′) R^(1″) R 1 H H H

2 H H H

3 H CH₃ H

4 H CH₃ CH₃

5 H H CO₂CH₃

6 H H H

7 H H H

8 H H CONH₂ Cbz 9 H H CONH₂ 2-quinolinylcarbonyl

TABLE 11

Entry R R′ X 1 R = H R′ = H X = H 2 R = Me R′ = Me X = H 3 R = H R′ = MeX = H 4 R = Me R′ = Me X = F 5 R = H R′ = Me X = F 6 R = Cbz R′ = Me X =H 7 R = H R′ = Bz X = H 8 R + R′ = pyrrole X = H

TABLE 12

Entry Acyl Group (R) 1 benzyloxycarbonyl 2 tert-butoxycarbonyl 3 acetyl4 2-quinoylcarbonyl 5 phenoxyacetyl 6 benzoyl 7 methyloxaloyl 8 pivaloyl9 trifluoracetyl 10 bromoacetyl 11 hydroxyacetyl 12 morpholinylacetyl 13N,N-dimethylaminoacetyl 14 N-benzylaminoacetyl 15 N-phenylaminoacetyl 16N-benzyl-N-methylaminoacetyl 17 N-methyl-N-(2-hydroxyethyl)aminoacetyl18 N-methylcarbamoyl 19 3-methylbutyryl 20 N-isobutylcarbamoyl 21succinoyl(3-carboxypropionyl) 22 carbamoyl 23 N-(2-indanyl)aminoacetyl

TABLE 13

Entry R³ R⁴  1 —CH₃ -n-Butyl  2 -i-Butyl —CH₃  3 -i-Butyl -n-Butyl  4-i-Propyl -n-Butyl  5 —C₆H₅ -n-Butyl  6

-n-Butyl  7

-n-Butyl  8

-n-Butyl  9 -i-Butyl -n-Propyl 10 -i-Butyl —CH₂CH(CH₃)₂ 11

-n-Butyl 12

-i-Propyl 13

—CH₂CH₂CH(CH₃)₂ 14 i-Butyl —CH₂CH₃ 15 i-Butyl —CH(CH₃)₂ 16 i-Butyl

17

—(CH₂)₂CH(CH₃)₂ 18 (CH₂)₂CH(CH₃)₂ —CH(CH₃)₂ 19 i-Butyl —CH(CH₃)₂ 20i-Butyl —C(CH₃)₃ 21

—C(CH₃)₃ 22 —(CH₂)₂CH(CH₃)₂ —C(CH₃)₃ 23 —CH₂C6H₅ —C(CH₃)₃ 24 —(CH₂)₂C₆H₅—C(CH₃)₃ 25 n-Butyl —C(CH₃)₃ 26 n-Pentyl —C(CH₃)₃ 27 n-Hexyl —C(CH₃)₃ 28

—C(CH₃)₃ 29 —CH₂C(CH₃)₃ —C(CH₃)₃ 30

—C(CH₃)₃ 31 —CH₂C₆H₅OCH₃(para) —C(CH₃)₃ 32

—C(CH₃)₃ 33

—C(CH₃)₃ 34 —(CH₂)₂C(CH₃)₃ —C(CH₃)₃ 35 —(CH₂)₄OH —C(CH₃)₃ 36

—C(CH₃)₃ 37

—C(CH₃)₃ 38 —CH₂CH(CH₃)₂ —C₆H₅ 39 i-amyl —CH₂C(CH₃)₃ 40

—CH₂C(CH₃)₃ 41

—CH₂C(CH₃)₃ 42 i-butyl —CH₂C(CH₃)₃ 43 —CH₂Ph —Ph 44

—Ph 45

—Ph 46

—Ph 47

—Ph 48

—Ph 49 —CH₂CH═CH₂ —Ph 50

—Ph 51

—Ph 52 —CH₂CH₂Ph —Ph 53 —CH₂CH₂CH₂CH₂OH —Ph 54 —CH₂CH₂N(CH₃)₂ —Ph 55

—Ph 56 —CH₃ —Ph 57 —CH₂CH₂CH₂SCH₃ —Ph 58 —CH₂CH₂CH₂S(O)₂CH₃ —Ph 59—CH₂CH₂CH(CH₃)₂

60 —CH₂CH₂CH(CH₃)₂

61 —CH₂CH₂CH(CH₃)₂ —CH₂CH₂CH₃ 62 —CH₂CH₂CH(CH₃)₂ —CH₃ 63 —CH₂CH₂CH(CH₃)₂

64 —CH₂CH₂CH(CH₃)₂

65 —CH₂CH₂CH(CH₃)₂

66 —CH₂CH₂CH(CH₃)₂

67 —CH₂CH₂CH(CH₃)₂

68 —CH₂CH₂CH(CH₃)₂

69 —CH₂CH₂CH(CH₃)₂

70 —CH₂CH₂CH(CH₃)₂

71 —CH₂CH₂CH(CH₃)₂

72 —CH₂CH₂CH(CH₃)₂

73 —CH₂CH₂CH(CH₃)₂

74 —CH₂CH₂CH(CH₃)₂

75 —CH₂CH(CH₃)₂

76 —CH₂CH(CH₃)₂

77 —CH₂CH(CH₃)₂

78 —CH₂CH(CH₃)₂

79 —CH₂CH₂CH₃

80 —CH₂CH₂CH₂CH₃

^(a)benzyloxycarbonyl ^(b)2-quinolinylcarbonyl

TABLE 14

Entry R¹ R³ 1 C(CH₃)₃ CH₂CH₂CH(CH₃)₂ 2 CH₂C≡CH CH₂CH₂CH(CH₃)₂ 3C(CH₃)₂(SCH₃) CH₂CH₂CH(CH₃)₂ 4 C(CH₃)₂(S[O]CH₃) CH₂CH₂CH(CH₃)₂ 5C(CH₃)₂(S[O]₂CH₃) CH₂CH₂CH(CH₃)₂ 6 C(CH₃)₃ CH₂CH(CH₃)₂ 7 C(CH₃)₃cyclohexyl 8 CH(CH₃)₂ CH₂CH(CH₃)₂ 9 CH(CH₂CH₃)(CH₃) CH₂CH(CH₃)₂

TABLE 14A

Entry R¹ R³ 1 C(CH₃)SCH₃ CH₂CH₂CH(CH₃)₂

TABLE 15

Ar

TABLE 16

R₁ R₈

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

H or CH₃

TABLE 16A

R

TABLE 16B

R

TABLE 16C

R

TABLE 16D

R

TABLE 16E

R

TABLE 16F

R

TABLE 16G

R

TABLE 16H

R

TABLE 16I

R

TABLE 16J

R

TABLE 16K

R

TABLE 16L

R

TABLE 16M

R

TABLE 16N

R

TABLE 17

A

TABLE 17A

R

R″ = —H or lower alkyl

TABLE 17B

R = H or OH R¹ = CH₃, NH₂, F, Cl or Br R² = H or CH₃

EXAMPLE 23

The compounds of the present invention are effective HIV proteaseinhibitors. Utilizing an enzyme assay as described below, the compoundsset forth in the examples herein disclosed inhibited the HIV enzyme. Thepreferred compounds of the present invention and their calculated IC₅₀(inhibiting concentration 50%, i.e., the concentration at which theinhibitor compound reduces enzyme activity by 50%) values are shown inTables 18 through 21. The enzyme method is described below. Thesubstrate is 2-Ile-Nle-Phe(p-NO₂)-Gln-ArgNH₂. The positive control isMVT-101 (Miller, M. et al, Science, 246, 1149 (1989)] The assayconditions are as follows:

Assay buffer:

20 mM sodium phosphate, pH 6.4

20% glycerol

1 mM EDTA

1 mM DTT

0.1% CHAPS

The above described substrate is dissolved in DMSO, then diluted 10 foldin assay buffer. Final substrate concentration in the assay is 80 μM.

HIV protease is diluted in the assay buffer to a final enzymeconcentration of 12.3 nanomolar, based on a molecular weight of 10,780.

The final concentration of DMSO is 14% and the final concentration ofglycerol is 18%. The test compound is dissolved in DMSO and diluted inDMSO to 10× the test concentration; 10 μl of the enzyme preparation isadded, the materials mixed and then the mixture is incubated at ambienttemperature for 15 minutes. The enzyme reaction is initiated by theaddition of 40 μl of substrate. The increase in fluorescence ismonitored at 4 time points (0, 8, 16 and 24 minutes) at ambienttemperature. Each assay is carried out in duplicate wells.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

TABLE 18A IC₅₀ Entry Compound (nanomolar)  1

16    2

1.5  3

1.4  4

27    5

19    6

10    7

3.6  8

4.2  9

3.5 10

100    11

81   12

20  

TABLE 19B Ex. Table Entry IC₅₀ (uM) or % inhib  6  1a  1 0.011  6  1a  20.010  6  1a  3 38% @ 1 uM, 79% @ 10 uM  6  1a  4 0.016  6  1a  5 0.10 6  1a  6 36% @ 10 uM  6  1a  7 0.0096  6  1a  39 0.016  6  1a  40 0.21 6  1a  41 24% @ 1 uM, 74% @ 10 uM  6  1a  50 42% @ 1 uM, 89% @ 10 uM  6 1a  51 31% @ 1 uM, 76% @ 10 uM  6  1a  52 39% @ 1 uM, 81% @ 10 uM  6 1a  53 0.049  6  1a  54 0.0028  6  1a  55 0.10  6  1a  56 0.0036 16  3 1 0.081 16  3  2 38% @ 0.1 uM, 90% @ 1.0 uM 16  3  4 0.0024 16  3  60.0018 16  3  8 0.003 16  3  10 0.0025 16  3  12 0.0016 16  4 102 0.001516  5  1 0.0014 16  5  14 0.0022 16  5  22 0.0018 16  5  33 0.0044 16  5 34 0.0020 16  7  31 0.0028 16  7  32 0.0015 16 11  1 0.13 16 11  9 41%@ 0.1 uM, 86% @ 1 uM 16 12  10 0.0033 16 14  3 0.0049 16 14  10 0.0032

TABLE 20 Table Entry IC₅₀ (uM) or % inhibtion 1A  3 0.02 5A  1 0.04 5A 3 0.02 5A  4 0.01 5A  5 0.026 5A  6 0.023 5A  7 0.007 5A  9 0.067 5A 110.018 5A 12 0.006 5A 13 0.0098 5A 14 0.049 5A 16 0.008 5A 17 59% @ 10 μM5A 18 0.13 5A 19 0.092 5A 20 85% @ 1 μM 5A 22 63% @ 1 μM 5A 24 0.047 5A25 0.014 5A 26 0.005 5A 28 0.015 5A 29 0.19 5A 30 0.03 5A 31 0.02

EXAMPLE 24

The effectiveness of various compounds were determined in theabove-described enzyme assay and in a CEM cell assay.

The HIV inhibition assay method of acutely infected cells is anautomated tetrazolium based colorimetric assay essentially that reportedby Pauwles et al, J. Virol. Methods, 20, 309-321 (1988). Assays wereperformed in 96-well tissue culture plates. CEM cells, a CD4⁺ cell line,were grown in RPMI-1640 medium (Gibco) supplemented with a 10% fetalcalf serum and were then treated with polybrene (2 μg/ml). An 80 μlvolume of medium containing 1×10⁴ cells was dispensed into each well ofthe tissue culture plate. To each well was added a 100 μl volume of testcompound dissolved in tissue culture medium (or medium without testcompound as a control) to achieve the desired final concentration andthe cells were incubated at 37° C. for 1 hour. A frozen culture of HIV-1was diluted in culture medium to a concentration of 5×10⁴ TCID₅₀ per ml(TCID₅₀=the dose of virus that infects 50% of cells in tissue culture),and a 20 μL volume of the virus sample (containing 1000 TCID₅₀ of virus)was added to wells containing test compound and to wells containing onlymedium (infected control cells). Several wells received culture mediumwithout virus (uninfected control cells). Likewise, the intrinsictoxicity of the test compound was determined by adding medium withoutvirus to several wells containing test compound. In summary, the tissueculture plates contained the following experiments:

Cells Drug Virus 1. + − − 2. + + − 3. + − + 4. + + +

In experiments 2 and 4 the final concentrations of test compounds were1, 10, 100 and 500 μg/ml. Either azidothymidine (AZT) or dideoxyinosine(ddI) was included as a positive drug control. Test compounds weredissolved in DMSO and diluted into tissue culture medium so that thefinal DMSO concentration did not exceed 1.5% in any case. DMSO was addedto all control wells at an appropriate concentration.

Following the addition of virus, cells were incubated at 37° C. in ahumidified, 5% CO₂ atmosphere for 7 days. Test compounds could be addedon days 0, 2 and 5 if desired. On day 7, post-infection, the cells ineach well were resuspended and a 100 μl sample of each cell suspensionwas removed for assay. A 20 μL volume of a 5 mg/ml solution of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) wasadded to each 100 μL cell suspension, and the cells were incubated for 4hours at 27° C. in a 5% CO₂ environment. During this incubation, MTT ismetabolically reduced by living cells resulting in the production in thecell of a colored formazan product. To each sample was added 100 μl of10% sodium dodecylsulfate in 0.01 N HCl to lyse the cells, and sampleswere incubated overnight. The absorbance at 590 nm was determined foreach sample using a Molecular Devices microplate reader. Absorbancevalues for each set of wells is compared to assess viral controlinfection, uninfected control cell response as well as test compound bycytotoxicity and antiviral efficacy.

TABLE 21 IC₅₀ EC₅₀ TD₅₀ Entry Compound (nM) (nM) (nM)  1

16 55    27  2

 1  5   203  3

 1 11   780  4

27 64    28  5

19 88    11  6

>100    380    425  7

 3 25    39  8

85 1200     24  9

53 398     15 10

45 700     12 11

 3 11    54 12

 2 12      7.5 13

 3 <16   14

 4 15 55,000 15

 5 38 16

 9 80 62,000 17

 4  5 59,000 18

 4 154  19

 8 377  20

 4 13 21

73 22

15 18 31,000 23

 2  8 24

 3 25

60 120  167,000  26

68 27

 5 177  300,000  28

14 76 213,000  29

 5 105  196,000  30

 6 154  154,000  31

10 32

 5 98 17,000 33

18 68 34

67 188  35

18 36

310  898  37

 7 <20   38

 4 1,100   39

16 269  40

 3 41

 3 11 42

 2 <20   43

 4 63 44

 4  8 45

 2  5 46

 2 <20   47

 3 <20   48

17 210  49

 6 <20   50

14 51

 9 <20   52

>100    53

21 54

10 55

37 56

 4 40 57

 4 <20   58

 2 70 59

 3 22 60

 5 60 61

16 62

28 63

 7 64

 7 65

 4 66

 4 67

 5 68

 7 69

 4 68 70

 5 30 71

 5 72

 5 42 73

 4 22 74

 3 75

 8 76

 5 77

 2 78

 3

The compounds of the present invention are effective antiviral compoundsand, in particular, are effective retroviral inhibitors as shown above.Thus, the subject compounds are effective HIV protease inhibitors. It iscontemplated that the subject compounds will also inhibit otherretroviruses such as other lentiviruses in particular other strains ofHIV, e.g. HIV-2, human T-cell leukemia virus, respiratory syncitialvirus, simia immunodeficiency virus, feline leukemia virus, felineimmuno-deficiency virus, hepadnavirus, cytomegalovirus and picornavirus.Thus, the subject compounds are effective in the treatment and/orproplylaxis of retroviral infections.

The subject compounds are also effective in preventing the growth ofretroviruses in a solution. Both human and animal cell cultures, such asT-lymphocyte cultures, are utilized for a variety of well knownpurposes, such as research and diagnostic procedures includingcalibrators and controls. Prior to and during the growth and storage ofa cell culture, the subject compounds may be added to the cell culturemedium at an effective concentration to prevent the unexpected orundesired replication of a retrovirus that may inadvertently orunknowingly be present in the cell culture. The virus may be presentoriginally in the cell culture, for example HIV is known to be presentin human T-lymphocytes long before it is detectable in blood, or throughexposure to the virus. This use of the subject compounds prevents theunknowing or inadvertent exposure of a potentially lethal retrovirus toa researcher or clinician.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or nonracemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, for example byformation of diastereoisomeric salts by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of Formula Iwith an optically pure acid in an activated form or an optically pureisocyanate. The synthesized diastereoisomers can be separated byconventional means such as chromatography, distillation, crystallizationor sublimation, and then hydrolyzed to deliver the enantiomerically purecompound. The optically active compounds of Formula I can likewise beobtained by utilizing optically active starting materials. These isomersmay be in the form of a free acid, a free base, an ester or a salt.

The compounds of the present invention can be used in the form of saltsderives from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Total daily dose administered to a host in single or divided doses maybe in amounts, for example, from 0.001 to 10 mg/kg body weight daily andmore usually 0.01 to 1 mg. Dosage unit compositions may contain suchamounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized andwhether the compound is administered as part of a drug combination.Thus, the dosage regimen actually employed may vary widely and thereforemay deviate from the preferred dosage regimen set forth above.

The compounds of the present invention may be administered orally,parenterally, by inhalation spray, rectally, or topically in dosage unitformulations containing conventional nontoxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles as desired. Topicaladministration may also involve the use of transdermal administrationsuch as transdermal patches or iontophoresis devices. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

While the compounds of ,the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more immunomodulators, antiviral agents or other antiinfectiveagents. For example, the compounds of the invention can be administeredin combination with AZT, DDI, DDC or with glucosidase inhibitors, suchas N-butyl-1-deoxynojirimycin or prodrugs thereof, for the prophylaxisand/or treatment of AIDS. When administered as a combination, thetherapeutic agents can be formulated as separate compositions which aregiven at the same time or different times, or the therapeutic agents canbe given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound represented by the formula (A):

or a pharmaceutically acceptable salt, prodrug, or ester thereof,wherein Y is a cycloalkyl, aryl, heterocyclyl, or heteroaryl R² is analkyl, aryl, cycloalkyl, cycloalkylalkyl or aralkyl radical, whichradical is optionally substituted with a radical selected from the groupconsisting of alkyl, halo, nitro, cyano, CF₃, —OR⁹, and —SR⁹, wherein R⁹is a radical selected from the group consisting of hydrogen and alkyl;R³ is a hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, heteroaralkyl, aminoalkyl or mono- or disubstitutedaminoalkyl radicals, wherein said substituents are selected from thegroup consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl and heterocycloalkylalkylradicals; or where said aminoalkyl radical is disubstituted, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical; R⁴ is an alkyl,haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, aralkenyl, heteroaralkyl, aminoalkyl or mono- ordisubstituted aminoalkyl radical, wherein said substituents are selectedfrom the group consisting of alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl andheterocycloalkylalkyl radicals; or where said aminoalkyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached, form a heterocycloalkyl or a heteroaryl radical. 2.The compound of claim 1 or a pharmaceutically acceptable salt, prodrug,or ester thereof, wherein: R² is an alkyl, aryl, cycloalkyl,cycloalkylalkyl or aralkyl radical, which radical is optionallysubstituted with a radical selected from the group consisting of alkyl,halo and —OR⁹, wherein R⁹ is a radical selected from the groupconsisting of hydrogen and alkyl; R³ is a hydrogen, alkyl, haloalkyl,alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl,alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl,aminoalkyl or mono- or disubstituted aminoalkyl radicals, wherein saidsubstituents are selected from the group consisting of alkyl, aralkyl,cycloalkyl and cycloalkylalkyl radicals; or where said aminoalkylradical is disubstituted, said substituents along with the nitrogen atomto which they are attached, form a heterocycloalkyl or a heteroarylradical; R⁴ is an alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, aralkenyl or heteroaralkylradical.
 3. The compound of claim 2 or a pharmaceutically acceptablesalt, prodrug, or ester thereof, wherein: R³ is a hydrogen, alkyl,haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl,alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl,aminoalkyl or mono- or dialkyl substituted aminoalkyl radical.
 4. Thecompound of claim 3 or a pharmaceutically acceptable salt, prodrug, orester thereof, wherein: R² is an alkyl, cycloalkylalkyl or aralkylradical, which radical is optionally substituted with a radical selectedfrom the group consisting of alkyl, halo and —OR⁹, where R⁹ is a radicalselected from the group consisting of hydrogen and alkyl; R³ is ahydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl,alkylthioalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl or mono-or dialkyl substituted aminoalkyl radical.
 5. The compound of claim 4 ora pharmaceutically acceptable salt, prodrug, or ester thereof, wherein:R² is butyl, cyclohexylmethyl, benzyl, 4-fluorobenzyl or naphthylmethyl;R³ is methyl, ethyl, propyl, butyl, pentyl, hexyl, isobutyl, iso-amyl,3-methoxypropyl, 3-methylthiopropyl, 4-methylthiobutyl,4-methylsulfonylbutyl, 2-dimethylaminoethyl, 2-(1-morpholino)ethyl,4-hydroxybutyl, allyl, propargyl, cyclohexylmethyl, cyclopropylmethyl,phenyl, benzyl, 4-fluorobenzyl, 4-methoxybenzyl, 1-phenylethyl,2-phenylethyl, naphthylmethyl, 3-pyridylmethyl or 4-pyridylmethyl; R⁴ ismethyl, ethyl, propyl, butyl, ethenyl, chloromethyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, chlorophenyl,fluorophenyl, hydroxyphenyl, methylphenyl, methoxyphenyl, ethoxyphenyl,methylthiophenyl, methylsulfoxyphenyl, methylsulfonylphenyl,acetamidophenyl, methoxycarbonylphenyl, dimethylaminophenyl,nitrophenyl, trifluoromethylphenyl, benzyl, 2-phenylethenyl or thienyl.6. The compound of claim 1 wherein the R² substituent has an (S)absolute stereochemical configuration and the adjacent hydroxyl grouphas an (R) stereochemical configuration.
 7. The compound of claim 1wherein Y is phenyl, methylphenyl, dimethylphenyl, methoxyphenyl,methylformamidinylphenyl, aminoformamidinylphenyl,flouroformamidinylphenyl, chloroformamidinylphenyl,bromoformamidinylphenyl, methylhydroxyformamidinylphenyl,aminohydroxyformamidinylphenyl, fluorohydroxyformamidinylphenyl,chlorohydroxyformamidinylphenyl, bromohydroxyformamidinylphenyl,oxopyridyl, pyrazinyl, pyrimidinyl, aminopyrazinyl, aminopyrimidinyl,methylpyrazinyl, methylpyrimidinyl, hydroxypyrazinyl,hydroxypyrimidinyl, furyl, furanyl, piperidinylpyridyl,morpholinylpyridinyl, piperazinylpyridinyl, methylpiperazinylpyridinyl,pyrrolidinylpyridinyl, oxazolyl, pyridyl, methylaminopyridyl,aminopyridyl, hydroxypyridyl, tetrahydrothiophenyl,oxotetrahydrothiophenyl, dioxotetrahydrothiophenyl, pyrrolidinyl,alkylpyrrolidinyl, tetrahydrofuryl, thienyl, thiazolyl, methylthiazolyl,aminothiazolyl, or dimethylaminothiazolyl.
 8. A method of inhibiting aretroviral protease comprising administering a compound represented bythe formula (A):

or a pharmaceutically acceptable salt, prodrug, or ester thereof,wherein Y is a cycloalkyl, aryl, heterocyclyl, or heteroaryl R² is analkyl, aryl, cycloalkyl, cycloalkylalkyl or aralkyl radical, whichradical is optionally substituted with a radical selected from the groupconsisting of alkyl, halo, nitro, cyano, CF₃, —OR⁹, and —SR⁹, wherein R⁹is a radical selected from the group consisting of hydrogen and alkyl;R³ is a hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, heteroaralkyl, aminoalkyl or mono- or disubstitutedaminoalkyl radicals, wherein said substituents are selected from thegroup consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl and heterocycloalkylalkylradicals; or where said aminoalkyl radical is disubstituted, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical; R⁴ is an alkyl,haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, aralkenyl, heteroaralkyl, aminoalkyl or mono- ordisubstituted aminoalkyl radical, wherein said substituents are selectedfrom the group consisting of alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl andheterocycloalkylalkyl radicals; or where said aminoalkyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached, form a heterocycloalkyl or a heteroaryl radical. 9.The method of claim 8 wherein the retroviral protease is HIV protease.10. A method of treating a retroviral infection comprising administeringan effective amount of a compound represented by the formula (A):

or a pharmaceutically acceptable salt, prodrug, or ester thereof,wherein Y is a cycloalkyl, aryl, heterocyclyl, or heteroaryl R² is analkyl, aryl, cycloalkyl, cycloalkylalkyl or aralkyl radical, whichradical is optionally substituted with a radical selected from the groupconsisting of alkyl, halo, nitro, cyano, CF₃, —OR⁹, and —SR⁹, wherein R⁹is a radical selected from the group consisting of hydrogen and alkyl;R³ is a hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, heteroaralkyl, aminoalkyl or mono- or disubstitutedaminoalkyl radicals, wherein said substituents are selected from thegroup consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl and heterocycloalkylalkylradicals; or where said aminoalkyl radical is disubstituted, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical; R⁴ is an alkyl,haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, aralkenyl, heteroaralkyl, aminoalkyl or mono- ordisubstituted aminoalkyl radical, wherein said substituents are selectedfrom the group consisting of alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl andheterocycloalkylalkyl radicals; or where said aminoalkyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached, form a heterocycloalkyl or a heteroaryl radical. 11.The method of claim 10 wherein the retroviral infection is an HIVinfection.
 12. A method of treating AIDS comprising administering aneffective amount of a pharmaceutical composition comprising a compoundrepresented by the formula (A):

or a pharmaceutically acceptable salt, prodrug, or ester thereof,wherein Y is a cycloalkyl, aryl, heterocyclyl, or heteroaryl R² is analkyl, aryl, cycloalkyl, cycloalkylalkyl or aralkyl radical, whichradical is optionally substituted with a radical selected from the groupconsisting of alkyl, halo, nitro, cyano, CF₃, —OR⁹, and —SR⁹, wherein R⁹is a radical selected from the group consisting of hydrogen and alkyl;R³ is a hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, heteroaralkyl, aminoalkyl or mono- or disubstitutedaminoalkyl radicals, wherein said substituents are selected from thegroup consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl and heterocycloalkylalkylradicals; or where said aminoalkyl radical is disubstituted, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical; R⁴ is an alkyl,haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl,aryl, aralkyl, aralkenyl, heteroaralkyl, aminoalkyl or mono- ordisubstituted aminoalkyl radical, wherein said substituents are selectedfrom the group consisting of alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl andheterocycloalkylalkyl radicals; or where said aminoalkyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached, form a heterocycloalkyl or a heteroaryl radical.